195 results on '"Takashi Matsuzaka"'
Search Results
2. Macrophage SREBP1 regulates skeletal muscle regeneration
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Yumiko Oishi, Hiroyuki Koike, Naoki Kumagami, Yoshimi Nakagawa, Masaya Araki, Yoshitaka Taketomi, Yoshimi Miki, Shigeru Matsuda, Hyeree Kim, Takashi Matsuzaka, Hitoshi Ozawa, Hitoshi Shimano, Makoto Murakami, and Ichiro Manabe
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macrophage ,SREBP (sterol regulatory element-binding protein) pathway ,EPA - 20:5n-3 ,skeletal muscle regeneration ,fatty acid metabolism ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Macrophages are essential for the proper inflammatory and reparative processes that lead to regeneration of skeletal muscle after injury. Recent studies have demonstrated close links between the function of activated macrophages and their cellular metabolism. Sterol regulatory element-binding protein 1 (SREBP1) is a key regulator of lipid metabolism and has been shown to affect the activated states of macrophages. However, its role in tissue repair and regeneration is poorly understood. Here we show that systemic deletion of Srebf1, encoding SREBP1, or macrophage-specific deletion of Srebf1a, encoding SREBP1a, delays resolution of inflammation and impairs skeletal muscle regeneration after injury. Srebf1 deficiency impairs mitochondrial function in macrophages and suppresses the accumulation of macrophages at sites of muscle injury. Lipidomic analyses showed the reduction of major phospholipid species in Srebf1-/- muscle myeloid cells. Moreover, diet supplementation with eicosapentaenoic acid restored the accumulation of macrophages and their mitochondrial gene expression and improved muscle regeneration. Collectively, our results demonstrate that SREBP1 in macrophages is essential for repair and regeneration of skeletal muscle after injury and suggest that SREBP1-mediated fatty acid metabolism and phospholipid remodeling are critical for proper macrophage function in tissue repair.
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- 2024
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3. Loss of CtBP2 may be a mechanistic link between metabolic derangements and progressive impairment of pancreatic β cell function
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Motohiro Sekiya, Yang Ma, Kenta Kainoh, Kenji Saito, Daichi Yamazaki, Tomomi Tsuyuzaki, Wanpei Chen, Putu Indah Paramita Adi Putri, Hiroshi Ohno, Takafumi Miyamoto, Yoshinori Takeuchi, Yuki Murayama, Yoko Sugano, Yoshinori Osaki, Hitoshi Iwasaki, Naoya Yahagi, Hiroaki Suzuki, Kaori Motomura, Takashi Matsuzaka, Kazuya Murata, Seiya Mizuno, Satoru Takahashi, and Hitoshi Shimano
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CP: Metabolism ,CP: Molecular biology ,Biology (General) ,QH301-705.5 - Abstract
Summary: The adaptive increase in insulin secretion in early stages of obesity serves as a safeguard mechanism to maintain glucose homeostasis that cannot be sustained, and the eventual decompensation of β cells is a key event in the pathogenesis of diabetes. Here we describe a crucial system orchestrated by a transcriptional cofactor CtBP2. In cultured β cells, insulin gene expression is coactivated by CtBP2. Global genomic mapping of CtBP2 binding sites identifies a key interaction between CtBP2 and NEUROD1 through which CtBP2 decompacts chromatin in the insulin gene promoter. CtBP2 expression is diminished in pancreatic islets in multiple mouse models of obesity, as well as human obesity. Pancreatic β cell-specific CtBP2-deficient mice manifest glucose intolerance with impaired insulin secretion. Our transcriptome analysis highlights an essential role of CtBP2 in the maintenance of β cell integrity. This system provides clues to the molecular basis in obesity and may be targetable to develop therapeutic approaches.
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- 2023
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4. P428: THE FATTY ACID ELONGASE ELOVL6 IS CRUCIAL FOR HEMATOPOIETIC STEM CELL ENGRAFTMENT AND LEUKEMIA PROPAGATION
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Yusuke Kiyoki, Takayasu Kato, Sakura Kito, Takashi Matsuzaka, Shin Morioka, Junko Sasaki, Kenichi Makishima, Tatsuhiro Sakamoto, Hidekazu Nishikii, Naoshi Obara, Mamiko Sakata-Yanagimoto, Takehiko Sasaki, Hitoshi Shimano, and Shigeru Chiba
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2023
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5. Predictive ability of current machine learning algorithms for type 2 diabetes mellitus: A meta‐analysis
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Satoru Kodama, Kazuya Fujihara, Chika Horikawa, Masaru Kitazawa, Midori Iwanaga, Kiminori Kato, Kenichi Watanabe, Yoshimi Nakagawa, Takashi Matsuzaka, Hitoshi Shimano, and Hirohito Sone
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Machine learning ,Meta‐analysis ,Type 2 diabetes mellitus ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Abstract Aims/Introduction Recently, an increasing number of cohort studies have suggested using machine learning (ML) to predict type 2 diabetes mellitus. However, its predictive ability remains inconclusive. This meta‐analysis evaluated the current ability of ML algorithms for predicting incident type 2 diabetes mellitus. Materials and Methods We systematically searched longitudinal studies published from 1 January 1950 to 17 May 2020 using MEDLINE and EMBASE. Included studies had to compare ML’s classification with the actual incidence of type 2 diabetes mellitus, and present data on the number of true positives, false positives, true negatives and false negatives. The dataset for these four values was pooled with a hierarchical summary receiver operating characteristic and a bivariate random effects model. Results There were 12 eligible studies. The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.81 (95% confidence interval [CI] 0.67–0.90), 0.82 [95% CI 0.74–0.88], 4.55 [95% CI 3.07–6.75] and 0.23 [95% CI 0.13–0.42], respectively. The area under the summarized receiver operating characteristic curve was 0.88 (95% CI 0.85–0.91). Conclusions Current ML algorithms have sufficient ability to help clinicians determine whether individuals will develop type 2 diabetes mellitus in the future. However, persons should be cautious before changing their attitude toward future diabetes risk after learning the result of the diabetes prediction test using ML algorithms.
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- 2022
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6. Macrophage specific restoration of the Nrf2 gene in whole-body knockout mice ameliorates steatohepatitis induced by lipopolysaccharide from Porphyromonas gingivalis through enhanced hepatic clearance.
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Kanako Chihara, Kosuke Okada, Fumihiko Uchida, Ikuru Miura, Shoichi Komine, Eiji Warabi, Takako Takayama, Hideo Suzuki, Takashi Matsuzaka, Naomi Ishibashi-Kanno, Kenji Yamagata, Toru Yanagawa, Hiroki Bukawa, and Junichi Shoda
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Medicine ,Science - Abstract
Lipopolysaccharide (LPS) derived from Porphyromonas gingivalis (P.g.), which causes periodontal disease, contributes to the development of non-alcoholic steatohepatitis (NASH). We investigated the role of Nrf2, an antioxidative stress sensor, in macrophages in the development of NASH induced by LPS from P.g. We generated macrophage-specific Nrf2 gene rescue mice (Nrf2-mRes), which express Nrf2 only in macrophages, using the cre/loxp system. Wild-type (WT) mice, whole body Nrf2-knockout (Nrf2-KO) mice, and Nrf2-mRes mice were fed a high-fat diet for 18 weeks, and LPS from P.g. was administered intraperitoneally for the last 6 weeks. Nrf2-KO mice developed severe steatohepatitis with liver inflammation and fibrosis compared with WT mice, and steatohepatitis was ameliorated in Nrf2-mRes mice. The mRNA expressions of Toll-like receptor (Tlr)-2, which activates inflammatory signaling pathways after LPS binding, and α-smooth muscle actin (αSma), which promotes hepatic fibrosis, were reduced in Nrf2-mRes mice compared with Nrf2-KO mice. The protein levels of LPS-binding protein in livers were increased in Nrf2-KO mice compared with WT mice; however, the levels were reduced in Nrf2-mRes mice despite similar numbers of F4/80 positive cells, which reflect macrophage/Kupffer cell infiltration into the livers. Nrf2 in macrophages ameliorates NASH through the increased hepatic clearance of LPS.
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- 2023
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7. Identification of key microRNAs regulating ELOVL6 and glioblastoma tumorigenesis
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Nurani Istiqamah, Takashi Matsuzaka, Momo Shimizu, Kaori Motomura, Hiroshi Ohno, Shiho Hasebe, Rahul Sharma, Yuka Okajima, Erika Matsuda, Song-Iee Han, Yuhei Mizunoe, Yoshinori Osaki, Yuichi Aita, Hiroaki Suzuki, Hirohito Sone, Yoshinori Takeuchi, Motohiro Sekiya, Naoya Yahagi, Yoshimi Nakagawa, and Hitoshi Shimano
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Cell proliferation ,Fatty acid ,Glioblastoma ,MicroRNA ,Migration ,Biochemistry ,QD415-436 ,Genetics ,QH426-470 - Abstract
ELOVL fatty acid elongase 6 (ELOVL6) controls cellular fatty acid (FA) composition by catalyzing the elongation of palmitate (C16:0) to stearate (C18:0) and palmitoleate (C16:1n-7) to vaccinate (C18:1n-7). Although the transcriptional regulation of ELOVL6 has been well studied, the post-transcriptional regulation of ELOVL6 is not fully understood. Therefore, this study aims to evaluate the role of microRNAs (miRNAs) in regulating human ELOVL6. Bioinformatic analysis identified five putative miRNAs: miR-135b-5p, miR-135a-5p, miR-125a-5p, miR-125b-5p, and miR-22–3p, which potentially bind ELOVL6 3′-untranslated region (UTR). Results from dual-luciferase assays revealed that these miRNAs downregulate ELOVL6 by directly interacting with the 3′-UTR of ELOVL6 mRNA. Moreover, miR-135b-5p and miR-135a-5p suppress cell proliferation and migration in glioblastoma multiforme cells by inhibiting ELOVL6 at the mRNA and protein levels. Taken together, our results provide novel regulatory mechanisms for ELOVL6 at the post-transcriptional level and identify potential candidates for the treatment of patients with glioblastoma multiforme.
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- 2023
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8. CREBH regulation of lipid metabolism through multifaceted functions that improve arteriosclerosis
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Yoshimi Nakagawa, Takashi Matsuzaka, and Hitoshi Shimano
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Published
- 2022
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9. A case of NASH with genetic predisposition successfully treated with an SGLT2 inhibitor: a possible involvement of mitochondrial dysfunction
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Rikako Nakajima, Motohiro Sekiya, Yasuhisa Furuta, Takafumi Miyamoto, Masashi Sato, Kuniaki Fukuda, Keiichiro Hattori, Yasuhito Suehara, Mamiko Sakata-Yanagimoto, Shigeru Chiba, Yuka Okajima, Takashi Matsuzaka, Satoru Takase, Mikio Takanashi, Hiroaki Okazaki, Yusuke Takashima, Mikiko Yuhara, Yuta Mitani, Nako Matsumoto, Yuki Murayama, Mariko Ohyama Osawa, Nami Ohuchi, Daichi Yamazaki, Sayuri Mori, Yoko Sugano, Yoshinori Osaki, Hitoshi Iwasaki, Hiroaki Suzuki, and Hitoshi Shimano
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
In this study, we herein describe a 47-year-old Japanese woman who manifested inheritable non-alcoholic steatohepatitis (NASH) and severe dyslipidemia. Interestingly, her NASH progression was ameliorated by treatment with a sodium– glucose co-transporter 2 (SGLT2) inhibitor. This inheritability prompted us to comprehensively decode her genomic information using whole-exome sequencing. We found the well-established I148M mutation in PNPLA3 as well as mutations in LGALS3 and PEMT for her NASH. Mutations in GCKR may contribute to both NASH and dyslipidemia. We further mined gene mutations potentially responsible for her manifestations that led to the identification of a novel M188fs mutation in MUL1 that may be causally associated with her mitochondrial dysfunction. Our case may provide some clues to better understand this spectrum of disease as well as the rationale for selecting medications.
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- 2022
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10. The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis
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Motohiro Sekiya, Kenta Kainoh, Takehito Sugasawa, Ryunosuke Yoshino, Takatsugu Hirokawa, Hiroaki Tokiwa, Shogo Nakano, Satoru Nagatoishi, Kouhei Tsumoto, Yoshinori Takeuchi, Takafumi Miyamoto, Takashi Matsuzaka, and Hitoshi Shimano
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Science - Abstract
Sensing of nutrient status coordinates the regulation of liver glucose and lipid metabolism, and is important for metabolic homeostasis. Here the authors report that transcriptional the corepressor CtBP2 can sense nutrient status and coordinate repression of liver glucose and lipid metabolism via Fox01 and SREBP1, respectively.
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- 2021
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11. Macrophages rely on extracellular serine to suppress aberrant cytokine production
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Kento Kurita, Hiroya Ohta, Ibuki Shirakawa, Miyako Tanaka, Yasuyuki Kitaura, Yorihiro Iwasaki, Takashi Matsuzaka, Hitoshi Shimano, Seiichiro Aoe, Hiroshi Arima, Yoshihiro Ogawa, Ayaka Ito, and Takayoshi Suganami
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Medicine ,Science - Abstract
Abstract A growing body of evidence indicates that cellular metabolism is involved in immune cell functions, including cytokine production. Serine is a nutritionally non-essential amino acid that can be generated by de novo synthesis and conversion from glycine. Serine contributes to various cellular responses, but the role in inflammatory responses remains poorly understood. Here, we show that macrophages rely on extracellular serine to suppress aberrant cytokine production. Depleting serine from the culture media reduced the cellular serine content in macrophages markedly, suggesting that macrophages depend largely on extracellular serine rather than cellular synthesis. Under serine deprivation, macrophages stimulated with lipopolysaccharide showed aberrant cytokine expression patterns, including a marked reduction of anti-inflammatory interleukin-10 expression and sustained expression of interleukine-6. Transcriptomic and metabolomics analyses revealed that serine deprivation causes mitochondrial dysfunction: reduction in the pyruvate content, the NADH/NAD+ ratio, the oxygen consumption rate, and the mitochondrial production of reactive oxygen species (ROS). We also found the role of mitochondrial ROS in appropriate cytokine production. Thus, our results indicate that cytokine production in macrophages is tightly regulated by the nutritional microenvironment.
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- 2021
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12. Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive InhibitionSummary
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Yoshimi Nakagawa, Yunong Wang, Song-iee Han, Kanako Okuda, Asayo Oishi, Yuka Yagishita, Kae Kumagai, Hiroshi Ohno, Yoshinori Osaki, Yuhei Mizunoe, Masaya Araki, Yuki Murayama, Hitoshi Iwasaki, Morichika Konishi, Nobuyuki Itoh, Takashi Matsuzaka, Hirohito Sone, Nobuhiro Yamada, and Hitoshi Shimano
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CREB3L3 ,SREBP ,Hyperlipidemia ,Enterohepatic Circulation ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. Methods: CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR−/− mice. These mice were fed with a Western diet to develop atherosclerosis. Results: CREB3L3 ablation in LDLR−/− mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly up-regulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)–mediated lipogenic and cholesterogenic genes and regulates intestinal liver X receptor–regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi and vice versa. Conclusions: CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions.
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- 2021
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13. FoxO-KLF15 pathway switches the flow of macronutrients under the control of insulin
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Yoshinori Takeuchi, Naoya Yahagi, Yuichi Aita, Zahra Mehrazad-Saber, Man Hei Ho, Yiren Huyan, Yuki Murayama, Akito Shikama, Yukari Masuda, Yoshihiko Izumida, Takafumi Miyamoto, Takashi Matsuzaka, Yasushi Kawakami, and Hitoshi Shimano
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Molecular biology ,Molecular network ,Diabetology ,Science - Abstract
Summary: KLF15 is a transcription factor that plays an important role in the activation of gluconeogenesis from amino acids as well as the suppression of lipogenesis from glucose. Here we identified the transcription start site of liver-specific KLF15 transcript and showed that FoxO1/3 transcriptionally regulates Klf15 gene expression by directly binding to the liver-specific Klf15 promoter. To achieve this, we performed a precise in vivo promoter analysis combined with the genome-wide transcription-factor-screening method “TFEL scan”, using our original Transcription Factor Expression Library (TFEL), which covers nearly all the transcription factors in the mouse genome. Hepatic Klf15 expression is significantly increased via FoxOs by attenuating insulin signaling. Furthermore, FoxOs elevate the expression levels of amino acid catabolic enzymes and suppress SREBP-1c via KLF15, resulting in accelerated amino acid breakdown and suppressed lipogenesis during fasting. Thus, the FoxO-KLF15 pathway contributes to switching the macronutrient flow in the liver under the control of insulin.
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- 2021
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14. Rapid manipulation of mitochondrial morphology in a living cell with iCMM
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Takafumi Miyamoto, Hideki Uosaki, Yuhei Mizunoe, Song-Iee Han, Satoi Goto, Daisuke Yamanaka, Masato Masuda, Yosuke Yoneyama, Hideki Nakamura, Naoko Hattori, Yoshinori Takeuchi, Hiroshi Ohno, Motohiro Sekiya, Takashi Matsuzaka, Fumihiko Hakuno, Shin-Ichiro Takahashi, Naoya Yahagi, Koichi Ito, and Hitoshi Shimano
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mitochondria ,mitochondrial morphology ,synthetic biocomputing device ,synthetic biology ,Boolean logic gate ,Biotechnology ,TP248.13-248.65 ,Biochemistry ,QD415-436 ,Science - Abstract
Summary: Engineered synthetic biomolecular devices that integrate elaborate information processing and precisely regulate living cell behavior have potential in various applications. Although devices that directly regulate key biomolecules constituting inherent biological systems exist, no devices have been developed to control intracellular membrane architecture, contributing to the spatiotemporal functions of these biomolecules. This study developed a synthetic biomolecular device, termed inducible counter mitochondrial morphology (iCMM), to manipulate mitochondrial morphology, an emerging informative property for understanding physiopathological cellular behaviors, on a minute timescale by using a chemically inducible dimerization system. Using iCMM, we determined cellular changes by altering mitochondrial morphology in an unprecedented manner. This approach serves as a platform for developing more sophisticated synthetic biomolecular devices to regulate biological systems by extending manipulation targets from conventional biomolecules to mitochondria. Furthermore, iCMM might serve as a tool for uncovering the biological significance of mitochondrial morphology in various physiopathological cellular processes. Motivation: Mitochondria exhibit a variety of morphologies depending on the physiopathological condition of the cell, but the significance of changes in mitochondrial morphology remains almost unresolved. Although a method to induce mitochondrial morphological changes by altering the expression of proteins involved in mitochondrial dynamics has been established, this method requires several hours or more to induce mitochondrial morphological changes. Accordingly, a method to induce mitochondrial morphological changes at any given point in time on a minute timescale is needed.
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- 2021
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15. Wogonin, a Compound in Scutellaria baicalensis, Activates ATF4–FGF21 Signaling in Mouse Hepatocyte AML12 Cells
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Yasunari Yamada, Hodaka Saito, Masaya Araki, Yuhei Tsuchimoto, Shin-ichi Muroi, Kyohei Suzuki, Kazufumi Toume, Jun-Dal Kim, Takashi Matsuzaka, Hirohito Sone, Hitoshi Shimano, and Yoshimi Nakagawa
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wogonin ,fibroblast growth factor ,activating transcription factor 4 ,WAKANYAKU ,Scutellaria baicalensis ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Fibroblast growth factor 21 (FGF21), which is mainly synthesized and secreted by the liver, plays a crucial role in systemic glucose and lipid metabolism, ameliorating metabolic diseases. In this study, we screened the WAKANYAKU library derived from medicinal herbs to identify compounds that can activate Fgf21 expression in mouse hepatocyte AML12 cells. We identified Scutellaria baicalensis root extract and one of its components, wogonin, as an activator of Fgf21 expression. Wogonin also enhanced the expression of activating transcription factor 4 (ATF4) by a mechanism other than ER stress. Knockdown of ATF4 by siRNA suppressed wogonin-induced Fgf21 expression, highlighting its essential role in wogonin’s mode of action. Thus, our results indicate that wogonin would be a strong candidate for a therapeutic to improve metabolic diseases by enhancing hepatic FGF21 production.
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- 2022
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16. New perspective on type 2 diabetes, dyslipidemia and non‐alcoholic fatty liver disease
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Takashi Matsuzaka and Hitoshi Shimano
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Published
- 2020
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17. CREBH Improves Diet-Induced Obesity, Insulin Resistance, and Metabolic Disturbances by FGF21-Dependent and FGF21-Independent Mechanisms
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Aoi Satoh, Song-iee Han, Masaya Araki, Yoshimi Nakagawa, Hiroshi Ohno, Yuhei Mizunoe, Kae Kumagai, Yuki Murayama, Yoshinori Osaki, Hitoshi Iwasaki, Motohiro Sekiya, Morichika Konishi, Nobuyuki Itoh, Takashi Matsuzaka, Hirohito Sone, and Hitoshi Shimano
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Science - Abstract
Summary: Mice overexpressing the nuclear form of CREBH mainly in the liver (CREBH-Tg) showed suppression of high-fat high-sucrose (HFHS) diet-induced obesity accompanied by an increase in plasma fibroblast growth factor 21 (FGF21) levels. CREBH overexpression induced browning in inguinal white adipose tissue (WAT) and whole-body energy expenditure, which was canceled in Fgf21−/− mice. Deficiency of FGF21 in CREBH-Tg mice mostly canceled the improvement of obesity, but the suppression of inflammation of epidermal WAT, amelioration of insulin resistance, and improvement of glucose metabolism still sustained. Kisspeptin 1 (Kiss1) was identified as a novel hormone target for CREBH to explain these FGF21-independent effects of CREBH. Knockdown of Kiss1 in HFHS-fed CREBH-Tg Fgf21−/− mice showed partially canceled improvement of glucose metabolism. Taken together, we propose that hepatic CREBH pleiotropically improves diet-induced obesity-mediated dysfunctions in peripheral tissues by improving systemic energy metabolism in FGF21-dependent and FGF21-independent mechanisms. : Obesity Medicine; Molecular Genetics Subject Areas: Obesity Medicine, Molecular Genetics
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- 2020
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18. Rho‐associated, coiled‐coil‐containing protein kinase 1 as a new player in the regulation of hepatic lipogenesis
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Takafumi Miyamoto, Takashi Matsuzaka, and Hitoshi Shimano
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Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Published
- 2019
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19. Carrot Consumption Frequency Associated with Reduced BMI and Obesity through the SNP Intermediary rs4445711
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Kazuya Fujihara, Shun Nogawa, Kenji Saito, Chika Horikawa, Yasunaga Takeda, Kaori Cho, Hajime Ishiguro, Satoru Kodama, Yoshimi Nakagawa, Takashi Matsuzaka, Hitoshi Shimano, and Hirohito Sone
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carrot intake ,body mass index ,single nucleotide polymorphism ,rs4445711 ,Nutrition. Foods and food supply ,TX341-641 - Abstract
It is unclear whether genetic interactions are involved in the association between vegetable intake and reduced body mass index (BMI) or obesity. We conducted a comprehensive search for single nucleotide polymorphisms (SNPs) which are associated with the interaction between vegetable intake frequency and BMI or obesity. We performed a genome-wide association analysis to evaluate the genetic interactions between self-reported intake of vegetables such as carrot, broccoli, spinach, other green vegetables (green pepper and green beans), pumpkin, and cabbage with BMI and obesity, which is defined as a BMI ≥ 25.0 kg/m2 in the Japanese population (n = 12,225). The mean BMI and prevalence of obesity was 23.9 ± 3.4 kg/m2 and 32.3% in men and 22.1 ± 3.8 kg/m2 and 17.3% in in women, respectively. A significant interaction was observed between rs4445711 and frequency of carrot intake on BMI (p = 4.5 × 10−8). This interaction was slightly attenuated after adjustment for age, sex, alcohol intake, smoking, physical activity and the frequency of total vegetable intake (p = 2.1 × 10−7). A significant interaction was also observed between rs4445711 and frequency of carrot intake on obesity (p = 2.5 × 10−8). No significant interactions that were the same as the interaction between frequency of carrot intake and rs4445711 were observed between the intake frequency of broccoli, spinach, other green vegetables, pumpkin or cabbage and BMI or obesity. The frequency of carrot consumption is implicated in reducing BMI by the intermediary of rs4445711. This novel genetic association may provide new clues to clarify the association between vegetable intake and BMI or obesity.
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- 2021
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20. Effects of K-877, a novel selective PPARα modulator, on small intestine contribute to the amelioration of hyperlipidemia in low-density lipoprotein receptor knockout mice
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Kenta Takei, Yoshimi Nakagawa, Yunong Wang, Song-iee Han, Aoi Satoh, Motohiro Sekiya, Takashi Matsuzaka, and Hitoshi Shimano
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PPARα ,SPPARMα ,HDL cholesterol ,Cholesterol absorption ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a well-known therapeutic target for treating hyperlipidemia. K-877 is a novel selective PPARα modulator (SPPARMα) that enhances PPARα transcriptional activity with high selectivity and potency, resulting in reduced plasma lipid levels. This study aimed to evaluate the effects of K-877 on hyperlipidemia in low-density lipoprotein receptor knockout (Ldlr−/−) mice, a mouse model of atherosclerosis. We revealed that K-877 administration significantly decreased plasma triglyceride (TG) and total cholesterol (TC) levels and increased plasma high-density lipoprotein cholesterol (HDL-C) levels in Ldlr−/− mice. K-877 administration to Ldlr−/− mice efficiently increased the gene expression of PPARα and its target genes related to fatty acid oxidation in the liver and small intestine. The same treatment significantly increased ATP-binding cassette a1 gene expression in the liver and small intestine and reduced Niemann Pick C1-like 1 gene expression in the small intestine, suggesting that K-877 administration induced HDL-C production in the liver and small intestine and reduced cholesterol absorption in the small intestine. In conclusion, K-877 administration had pronounced effects on the liver and small intestine in Ldlr−/− mice. K-877 is an attractive PPARα-modulating drug for treating hyperlipidemia that works equally well in both the liver and small intestine.
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- 2017
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21. Intestinal CREBH overexpression prevents high-cholesterol diet-induced hypercholesterolemia by reducing Npc1l1 expression
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Takuya Kikuchi, Kana Orihara, Fusaka Oikawa, Song-iee Han, Motoko Kuba, Kanako Okuda, Aoi Satoh, Yoshinori Osaki, Yoshinori Takeuchi, Yuichi Aita, Takashi Matsuzaka, Hitoshi Iwasaki, Shigeru Yatoh, Motohiro Sekiya, Naoya Yahagi, Hiroaki Suzuki, Hirohito Sone, Yoshimi Nakagawa, Nobuhiro Yamada, and Hitoshi Shimano
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Internal medicine ,RC31-1245 - Abstract
Objective: The transcription factor cyclic AMP-responsive element-binding protein H (CREBH, encoded by Creb3l3) is highly expressed in the liver and small intestine. Hepatic CREBH contributes to glucose and triglyceride metabolism by regulating fibroblast growth factor 21 (Fgf21) expression. However, the intestinal CREBH function remains unknown. Methods: To investigate the influence of intestinal CREBH on cholesterol metabolism, we compared plasma, bile, fecal, and tissue cholesterol levels between wild-type (WT) mice and mice overexpressing active human CREBH mainly in the small intestine (CREBH Tg mice) under different dietary conditions. Results: Plasma cholesterol, hepatic lipid, and cholesterol crystal formation in the gallbladder were lower in CREBH Tg mice fed a lithogenic diet (LD) than in LD-fed WTs, while fecal cholesterol output was higher in the former. These results suggest that intestinal CREBH overexpression suppresses cholesterol absorption, leading to reduced plasma cholesterol, limited hepatic supply, and greater excretion. The expression of Niemann–Pick C1-like 1 (Npc1l1), a rate-limiting transporter mediating intestinal cholesterol absorption, was reduced in the small intestine of CREBH Tg mice. Adenosine triphosphate-binding cassette transporter A1 (Abca1), Abcg5/8, and scavenger receptor class B, member 1 (Srb1) expression levels were also reduced in CREBH Tg mice. Promoter assays revealed that CREBH directly regulates Npc1l1 expression. Conversely, CREBH null mice exhibited higher intestinal Npc1l1 expression, elevated plasma and hepatic cholesterol, and lower fecal output. Conclusion: Intestinal CREBH regulates dietary cholesterol flow from the small intestine by controlling the expression of multiple intestinal transporters. We propose that intestinal CREBH could be a therapeutic target for hypercholesterolemia. Keywords: CREBH, Npc1l1, Cholesterol, Intestine
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- 2016
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22. KLF15 Enables Rapid Switching between Lipogenesis and Gluconeogenesis during Fasting
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Yoshinori Takeuchi, Naoya Yahagi, Yuichi Aita, Yuki Murayama, Yoshikazu Sawada, Xiaoying Piao, Naoki Toya, Yukari Oya, Akito Shikama, Ayako Takarada, Yukari Masuda, Makiko Nishi, Midori Kubota, Yoshihiko Izumida, Takashi Yamamoto, Motohiro Sekiya, Takashi Matsuzaka, Yoshimi Nakagawa, Osamu Urayama, Yasushi Kawakami, Yoko Iizuka, Takanari Gotoda, Keiji Itaka, Kazunori Kataoka, Ryozo Nagai, Takashi Kadowaki, Nobuhiro Yamada, Yuan Lu, Mukesh K. Jain, and Hitoshi Shimano
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Biology (General) ,QH301-705.5 - Abstract
Hepatic lipogenesis is nutritionally regulated (i.e., downregulated during fasting and upregulated during the postprandial state) as an adaptation to the nutritional environment. While alterations in the expression level of the transcription factor SREBP-1c are known to be critical for nutritionally regulated lipogenesis, upstream mechanisms governing Srebf1 expression remain unclear. Here, we show that the fasting-induced transcription factor KLF15, a key regulator of gluconeogenesis, forms a complex with LXR/RXR, specifically on the Srebf1 promoter. This complex recruits the corepressor RIP140 instead of the coactivator SRC1, resulting in reduced Srebf1 and thus downstream lipogenic enzyme expression during the early and euglycemic period of fasting prior to hypoglycemia and PKA activation. Through this mechanism, KLF15 overexpression specifically ameliorates hypertriglyceridemia without affecting LXR-mediated cholesterol metabolism. These findings reveal a key molecular link between glucose and lipid metabolism and have therapeutic implications for the treatment of hyperlipidemia.
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- 2016
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23. 1,8-Cineole Ameliorates Steatosis of Pten Liver Specific KO Mice via Akt Inactivation
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Soichiro Murata, Koichi Ogawa, Takashi Matsuzaka, Mitsuru Chiba, Ken Nakayama, Kenichi Iwasaki, Tomohiro Kurokawa, Naoki Sano, Tomohito Tanoi, and Nobuhiro Ohkohchi
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1,8-cineole ,NASH ,PTEN ,Akt ,LXR alpha ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Hepatocyte-specific Phosphatase and tensin homolog (Pten)-knockout (KO) mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). 1,8-cineole is a monoterpene oxide and it has several biological effects including hepatoprotective effects. In this study we revealed that 1,8-cineole ameliorates NASH of Pten KO mice. Pten KO mice were assigned to a control group without any medication or to a 1,8-cineole group injected with 50 mg/kg i.p. twice per week for eight weeks. At eight weeks, livers from each group were processed to measure triglyceride (TG) content, gene expression analysis, western blot analysis, and histological examination including Oil red O staining. 1,8-cineole ameliorated hepatic steatosis in Pten KO mice, revealed by TG content and Oil red O staining. Moreover, 1,8-cineole downregulated collagen 1a1 expression and improved liver fibrosis. Thus, 1,8-cineole has potential as a candidate to treat NASH by inactivating the Akt/PI3-kinase pathway.
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- 2015
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24. Elongation of Long‐Chain Fatty Acid Family Member 6 (Elovl6)‐Driven Fatty Acid Metabolism Regulates Vascular Smooth Muscle Cell Phenotype Through AMP‐Activated Protein Kinase/Krüppel‐Like Factor 4 (AMPK/KLF4) Signaling
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Hiroaki Sunaga, Hiroki Matsui, Saki Anjo, Mas Risky A. A. Syamsunarno, Norimichi Koitabashi, Tatsuya Iso, Takashi Matsuzaka, Hitoshi Shimano, Tomoyuki Yokoyama, and Masahiko Kurabayashi
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Elovl6 ,fatty acid ,neointimal hyperplasia ,proliferation ,smooth muscle cell ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
BackgroundFatty acids constitute the critical components of cell structure and function, and dysregulation of fatty acid composition may exert diverging vascular effects including proliferation, migration, and differentiation of vascular smooth muscle cells (VSMCs). However, direct evidence for this hypothesis has been lacking. We investigated the role of elongation of long‐chain fatty acid member 6 (Elovl6), a rate‐limiting enzyme catalyzing the elongation of saturated and monounsaturated long‐chain fatty acid, in the regulation of phenotypic switching of VSMC. Methods and ResultsNeointima formation following wire injury was markedly inhibited in Elovl6‐null (Elovl6−/−) mice, and cultured VSMCs with siRNA‐mediated knockdown of Elovl6 was barely responsive to PDGF‐BB. Elovl6 inhibition induced cell cycle suppressors p53 and p21 and reduced the mammalian targets of rapamycin (mTOR) phosphorylation and VSMC marker expression. These changes are ascribed to increased palmitate levels and reduced oleate levels, changes that lead to reactive oxygen species (ROS) production and resulting AMP‐activated protein kinase (AMPK) activation. Notably, Elovl6 inhibition robustly induced the pluripotency gene Krüppel‐like factor 4 (KLF4) expression in VSMC, and KLF4 knockdown significantly attenuated AMPK‐induced phenotypic switching of VSMC, indicating that KLF4 is a bona fide target of AMPK. ConclusionsWe demonstrate for the first time that dysregulation of Elovl6‐driven long‐chain fatty acid metabolism induces phenotypic switching of VSMC via ROS production and AMPK/KLF4 signaling that leads to growth arrest and downregulation of VSMC marker expression. The modulation of Elovl6‐mediated cellular processes may provide an intriguing approach for tackling atherosclerosis and postangioplasty restenosis.
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- 2016
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25. Different Effects of Eicosapentaenoic and Docosahexaenoic Acids on Atherogenic High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease in Mice.
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Noriko Suzuki-Kemuriyama, Takashi Matsuzaka, Motoko Kuba, Hiroshi Ohno, Song-Iee Han, Yoshinori Takeuchi, Masaaki Isaka, Kazuto Kobayashi, Hitoshi Iwasaki, Shigeru Yatoh, Hiroaki Suzuki, Katsuhiro Miyajima, Dai Nakae, Naoya Yahagi, Yoshimi Nakagawa, Hirohito Sone, Nobuhiro Yamada, and Hitoshi Shimano
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Medicine ,Science - Abstract
Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, can progress to steatohepatitis (NASH) and advanced liver damage, such as that from liver cirrhosis and cancer. Recent studies have shown the benefits of consuming n-3 polyunsaturated fatty acids (PUFAs) for the treatment of NAFLD. In the present study, we investigated and compared the effects of the major n-3 PUFAs-eicosapentaenoic acid (EPA, C20:5) and docosahexaenoic acid (DHA, C22:6)-in preventing atherogenic high-fat (AHF) diet-induced NAFLD. Mice were fed the AHF diet supplemented with or without EPA or DHA for four weeks. Both EPA and DHA reduced the pathological features of AHF diet-induced NASH pathologies such as hepatic lobular inflammation and elevated serum transaminase activity. Intriguingly, EPA had a greater hepatic triacylglycerol (TG)-reducing effect than DHA. In contrast, DHA had a greater suppressive effect than EPA on AHF diet-induced hepatic inflammation and ROS generation, but no difference in fibrosis. Both EPA and DHA could be effective for treatment of NAFLD and NASH. Meanwhile, the two major n-3 polyunsaturated fatty acids might differ in a relative contribution to pathological intermediate steps towards liver fibrosis.
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- 2016
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26. Crucial Role of Elovl6 in Chondrocyte Growth and Differentiation during Growth Plate Development in Mice.
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Manami Kikuchi, Masako Shimada, Takashi Matsuzaka, Kiyoaki Ishii, Yoshimi Nakagawa, Misa Takayanagi, Nobuhiro Yamada, and Hitoshi Shimano
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Medicine ,Science - Abstract
ELOVL family member 6, elongation of very long chain fatty acids (Elovl6) is a microsomal enzyme, which regulates the elongation of C12-16 saturated and monounsaturated fatty acids. Elovl6 has been shown to be associated with various pathophysiologies including insulin resistance, atherosclerosis, and non-alcoholic steatohepatitis. To investigate a potential role of Elovl6 during bone development, we here examined a skeletal phenotype of Elovl6 knockout (Elovl6-/-) mice. The Elovl6-/- skeleton was smaller than that of controls, but exhibited no obvious patterning defects. Histological analysis revealed a reduced length of proliferating and an elongated length of hypertrophic chondrocyte layer, and decreased trabecular bone in Elovl6-/- mice compared with controls. These results were presumably due to a modest decrease in chondrocyte proliferation and accelerated differentiation of cells of the chondrocyte lineage. Consistent with the increased length of the hypertrophic chondrocyte layer in Elovl6-/- mice, Collagen10α1 was identified as one of the most affected genes by ablation of Elovl6 in chondrocytes. Furthermore, this elevated expression of Collagen10α1 of Elovl6-null chondrocytes was likely associated with increased levels of Foxa2/a3 and Mef2c mRNA expression. Relative increases in protein levels of nuclear Foxa2 and cytoplasmic histone deacethylase 4/5/7 were also observed in Elovl6 knockdown cells of the chondrocyte lineage. Collectively, our data suggest that Elovl6 plays a critical role for proper development of embryonic growth plate.
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- 2016
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27. The Peroxisome Proliferator-Activated Receptor α (PPARα) Agonist Pemafibrate Protects against Diet-Induced Obesity in Mice
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Masaya Araki, Yoshimi Nakagawa, Asayo Oishi, Song-iee Han, Yunong Wang, Kae Kumagai, Hiroshi Ohno, Yuhei Mizunoe, Hitoshi Iwasaki, Motohiro Sekiya, Takashi Matsuzaka, and Hitoshi Shimano
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SPPARMα ,pemafibrate ,PPARα ,FGF21 ,obesity ,lipid metabolism ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a therapeutic target for hyperlipidemia. Pemafibrate (K-877) is a new selective PPARα modulator activating PPARα transcriptional activity. To determine the effects of pemafibrate on diet-induced obesity, wild-type mice were fed a high-fat diet (HFD) containing pemafibrate for 12 weeks. Like fenofibrate, pemafibrate significantly suppressed HFD-induced body weight gain; decreased plasma glucose, insulin and triglyceride (TG) levels; and increased plasma fibroblast growth factor 21 (FGF21). However, compared to the dose of fenofibrate, a relatively low dose of pemafibrate showed these effects. Pemafibrate activated PPARα transcriptional activity in the liver, increasing both hepatic expression and plasma levels of FGF21. Additionally, pemafibrate increased the expression of genes involved in thermogenesis and fatty acid oxidation, including Ucp1, Cidea and Cpt1b in inguinal adipose tissue (iWAT) and the mitochondrial marker Elovl3 in brown adipose tissue (BAT). Therefore, pemafibrate activates thermogenesis in iWAT and BAT by increasing plasma levels of FGF21. Additionally, pemafibrate induced the expression of Atgl and Hsl in epididymal white adipose tissue, leading to the activation of lipolysis. Taken together, pemafibrate suppresses diet-induced obesity in mice and improves their obesity-related metabolic abnormalities. We propose that pemafibrate may be useful for the suppression and improvement of obesity-induced metabolic abnormalities.
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- 2018
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28. Protein kinase Cbeta mediates hepatic induction of sterol-regulatory element binding protein-1c by insulin
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Takashi Yamamoto, Kazuhisa Watanabe, Noriyuki Inoue, Yoshimi Nakagawa, Naomi Ishigaki, Takashi Matsuzaka, Yoshinori Takeuchi, Kazuto Kobayashi, Shigeru Yatoh, Akimitsu Takahashi, Hiroaki Suzuki, Naoya Yahagi, Takanari Gotoda, Nobuhiro Yamada, and Hitoshi Shimano
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SREBP ,lipogenesis ,fatty acid ,triglyceride ,glucose ,Biochemistry ,QD415-436 - Abstract
Sterol-regulatory element binding protein-1c (SREBP-1c) is a transcription factor that controls lipogenesis in the liver. Hepatic SREBP-1c is nutritionally regulated, and its sustained activation causes hepatic steatosis and insulin resistance. Although regulation of SREBP-1c is known to occur at the transcriptional level, the precise mechanism by which insulin signaling activates SREBP-1c promoter remains to be elucidated. Here we show that protein kinase C beta (PKCbeta) is a key mediator of insulin-mediated activation of hepatic SREBP-1c and its target lipogenic genes. Activation of SREBP-1c in the liver of refed mice was suppressed by either adenoviral RNAi-mediated knockdown or dietary administration of a specific inhibitor of protein kinase C beta. The effect of PKCbeta inhibition was cancelled in insulin depletion by streptozotocin (STZ) treatment of mice. Promoter analysis indicated that PKCbeta activates SREBP-1c promoter through replacement of Sp3 by Sp1 for binding to the GC box in the sterol regulatory element (SRE) complex, a key cis-element of SREBP-1c promoter. Knockdown of Sp proteins demonstrated that Sp3 and Sp1 play reciprocally negative and positive roles in nutritional regulation of SREBP-1c, respectively. This new understanding of PKCbeta involvement in nutritional regulation of SREBP-1c activation provides a new aspect of PKCbeta inhibition as a potential therapeutic target for diabetic complications.
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- 2010
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29. Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity
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Mayumi Ishikawa, Yuko Iwasaki, Shigeru Yatoh, Toyonori Kato, Shin Kumadaki, Noriyuki Inoue, Takashi Yamamoto, Takashi Matsuzaka, Yoshimi Nakagawa, Naoya Yahagi, Kazuto Kobayashi, Akimitsu Takahashi, Nobuhiro Yamada, and Hitoshi Shimano
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transcription factors ,sterol-regulatory element binding protein ,triglycerides ,Biochemistry ,QD415-436 - Abstract
To determine the role of cholesterol synthesis in pancreatic β-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) specifically in β-cells (TgRIP-SREBP-2) was developed and analyzed. Expression of nuclear human SREBP-2 in β-cells resulted in severe diabetes as evidenced by greater than 5-fold elevations in glycohemoglobin compared with C57BL/6 controls. Diabetes in TgRIP-SREBP-2 mice was primarily due to defects in glucose- and potassium-stimulated insulin secretion as determined by glucose tolerance test. Isolated islets of TgSREBP-2 mice were fewer in number, smaller, deformed, and had decreased insulin content. SREBP-2-expressing islets also contained increased esterified cholesterol and unchanged triglycerides with reduced ATP levels. Consistently, these islets exhibited elevated expression of HMG-CoA synthase and reductase and LDL receptor, with suppression of endogenous SREBPs. Genes involved in β-cell differentiation, such as PDX1 and BETA2, were suppressed, explaining loss of β-cell mass, whereas IRS2 expression was not affected. These phenotypes were dependent on the transgene expression. Taken together, these results indicate that activation of SREBP-2 in β-cells caused severe diabetes by loss of β-cell mass with accumulation of cholesterol, providing a new lipotoxic model and a potential link of disturbed cholesterol metabolism to impairment of β-cell function.
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- 2008
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30. SREBP-1-independent regulation of lipogenic gene expression in adipocytes
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Motohiro Sekiya, Naoya Yahagi, Takashi Matsuzaka, Yoshinori Takeuchi, Yoshimi Nakagawa, Haruka Takahashi, Hiroaki Okazaki, Yoko Iizuka, Ken Ohashi, Takanari Gotoda, Shun Ishibashi, Ryozo Nagai, Tsutomu Yamazaki, Takashi Kadowaki, Nobuhiro Yamada, Jun-ichi Osuga, and Hitoshi Shimano
- Subjects
sterol regulatory element-binding protein ,lipogenesis ,fatty acid synthase ,Biochemistry ,QD415-436 - Abstract
Sterol regulatory element-binding protein (SREBP)-1c is now well established as a key transcription factor for the regulation of lipogenic enzyme genes such as FAS in hepatocytes. Meanwhile, the mechanisms of lipogenic gene regulation in adipocytes remain unclear. Here, we demonstrate that those in adipocytes are independent of SREBP-1c. In adipocytes, unlike in hepatocytes, the stimulation of SREBP-1c expression by liver X receptor agonist does not accompany lipogenic gene upregulation, although nuclear SREBP-1c protein is concomitantly increased, indicating that the activation process of SREBP-1c by the cleavage system is intact in adipocytes. Supportively, transcriptional activity of the mature form of SREBP-1c for the FAS promoter was negligible when measured by reporter analysis. As an underlying mechanism, accessibility of SREBP-1c to the functional elements was involved, because chromatin immunoprecipitation assays revealed that SREBP-1c does not bind to the functional SRE/E-box site on the FAS promoter in adipocytes. Moreover, genetic disruption of SREBP-1 did not cause any changes in lipogenic gene expression in adipose tissue. In summary, in adipocytes, unlike in hepatocytes, increments in nuclear SREBP-1c are not accompanied by transactivation of lipogenic genes; thus, SREBP-1c is not committed to the regulation of lipogenesis.
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- 2007
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31. Transcriptional activities of nuclear SREBP-1a, -1c, and -2 to different target promoters of lipogenic and cholesterogenic genes
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Michiyo Amemiya-Kudo, Hitoshi Shimano, Alyssa H. Hasty, Naoya Yahagi, Tomohiro Yoshikawa, Takashi Matsuzaka, Hiroaki Okazaki, Yoshiaki Tamura, Yoko Iizuka, Ken Ohashi, Jun-ichi Osuga, Kenji Harada, Takanari Gotoda, Ryuichiro Sato, Satoshi Kimura, Shun Ishibashi, and Nobuhiro Yamada
- Subjects
lipogenesis ,cholesterol ,triglycerides ,fatty acids ,transcription factors ,Biochemistry ,QD415-436 - Abstract
Recent studies on the in vivo roles of the sterol regulatory element binding protein (SREBP) family indicate that SREBP-2 is more specific to cholesterogenic gene expression whereas SREBP-1 targets lipogenic genes. To define the molecular mechanism involved in this differential regulation, luciferase-reporter gene assays were performed in HepG2 cells to compare the transactivities of nuclear SREBP-1a, -1c, and -2 on a battery of SREBP-target promoters containing sterol regulatory element (SRE), SRE-like, or E-box sequences. The results show first that cholesterogenic genes containing classic SREs in their promoters are strongly and efficiently activated by both SREBP-1a and SREBP-2, but not by SREBP-1c. Second, an E-box containing reporter gene is much less efficiently activated by SREBP-1a and -1c, and SREBP-2 was inactive in spite of its ability to bind to the E-box. Third, promoters of lipogenic enzymes containing variations of SRE (SRE-like sequences) are strongly activated by SREBP-1a, and only modestly and equally by both SREBP-1c and -2. Finally, substitution of the unique tyrosine residue within the basic helix-loop-helix (bHLH) portion of nuclear SREBPs with arginine, the conserved residue found in all other bHLH proteins, abolishes the transactivity of all SREBPs for SRE, and conversely results in markedly increased activity of SREBP-1 but not activity of SREBP-2 for E-boxes.These data demonstrate the different specificity and affinity of nuclear SREBP-1 and -2 for different target DNAs, explaining a part of the mechanism behind the differential in vivo regulation of cholesterogenic and lipogenic enzymes by SREBP-1 and -2, respectively.
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- 2002
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32. Cloning and characterization of a mammalian fatty acyl-CoA elongase as a lipogenic enzyme regulated by SREBPs
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Takashi Matsuzaka, Hitoshi Shimano, Naoya Yahagi, Tomohiro Yoshikawa, Michiyo Amemiya-Kudo, Alyssa H. Hasty, Hiroaki Okazaki, Yoshiaki Tamura, Yoko Iizuka, Ken Ohashi, Jun-ichi Osuga, Akimitsu Takahashi, Shigeru Yato, Hirohito Sone, Shun Ishibashi, and Nobuhiro Yamada
- Subjects
sterol regulatory element-binding protein ,lipogenesis ,nutrition ,Biochemistry ,QD415-436 - Abstract
The mammalian enzyme involved in the final elongation of de novo fatty acid biosynthesis following the building of fatty acids to 16 carbons by fatty acid synthase has yet to be identified. In the process of searching for genes activated by sterol regulatory element-binding protein 1 (SREBP-1) by using DNA microarray, we identified and characterized a murine cDNA clone that is highly similar to a fatty acyl-CoA elongase gene family such as Cig30, Sscs, and yeast ELOs. Studies on the cells overexpressing the full-length cDNA indicate that the encoded protein, designated fatty acyl-CoA elongase (FACE), has a FACE activity specific for long-chains; C12-C16 saturated- and monosaturated-fatty acids. Hepatic expression of this identified gene was consistently activated in the livers of transgenic mice overexpressing nuclear SREBP-1a, -1c, or -2. FACE mRNA levels are markedly induced in a refed state after fasting in the liver and adipose tissue. This refeeding response is significantly reduced in SREBP-1 deficient mice. Dietary PUFAs caused a profound suppression of this gene expression, which could be restored by SREBP-1c overexpression. Hepatic FACE expression was also highly up-regulated in leptin-deficient ob/ob mice. Hepatic FACE mRNA was markedly increased by administration of a pharmacological agonist of liver X-activated receptor (LXR), a dominant activator for SREBP-1c expression.These data indicated that this elongase is a new member of mammalian lipogenic enzymes regulated by SREBP-1, playing an important role in de novo synthesis of long-chain saturated and monosaturated fatty acids in conjunction with fatty acid synthase and stearoyl-CoA desaturase.
- Published
- 2002
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33. Dual regulation of mouse Δ5- and Δ6-desaturase gene expression by SREBP-1 and PPARα
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Takashi Matsuzaka, Hitoshi Shimano, Naoya Yahagi, Michiyo Amemiya-Kudo, Tomohiro Yoshikawa, Alyssa H. Hasty, Yoshiaki Tamura, Jun-ichi Osuga, Hiroaki Okazaki, Yoko Iizuka, Akimitsu Takahashi, Hirohito Sone, Takanari Gotoda, Shun Ishibashi, and Nobuhiro Yamada
- Subjects
lipogenesis ,nutrition ,polyunsaturated fatty acids ,sterol regulatory element-binding protein ,Biochemistry ,QD415-436 - Abstract
In the process of seeking sterol regulatory element-binding protein 1a (SREBP-1a) target genes, we identified and cloned a cDNA clone encoding mouse Δ5-desaturase (D5D). The hepatic expression of D5D as well as Δ6-desaturase (D6D) was highly activated in transgenic mice overexpressing nuclear SREBP-1a, -1c, and -2. Disruption of the SREBP-1 gene significantly reduced the expression of both desaturases in the livers of SREBP-1-deficient mice refed after fasting. The hepatic expression of both desaturases was downregulated by dietary PUFA, which were reported to suppress SREBP-1c gene expression. Sustained expression of hepatic nuclear SREBP-1c protein in the transgenic mice abolished the PUFA suppression of both desaturases. Although these data suggested that SREBP-1c regulates D5D and D6D expression, there was no difference in either the D5D or D6D mRNA level between fasted and refed normal mouse livers, indicating a mechanism for fasting induction of both desaturases. Administration of fibrate, a pharmacological ligand for peroxisome proliferator activating receptor α (PPARα), caused a significant increase in expression of both desaturases. The data suggested that D5D and D6D expression is dually regulated by SREBP-1c and PPARα, two reciprocal transcription factors for fatty acid metabolism, and could be involved in lipogenic gene regulation by producing PUFA. —Matsuzaka, T., H. Shimano, N. Yahagi, M. Amemiya-Kudo, T. Yoshikawa, A. H. Hasty, Y. Tamura, J-i. Osuga, H. Okazaki, Y. Iizuka, A. Takahashi, H. Sone, T. Gotoda, S. Ishibashi, and N. Yamada. Dual regulation of mouse Δ5- and Δ6-desaturase gene expression by SREBP-1 and PPARα. J. Lipid Res. 2002. 43: 107–114.
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- 2002
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34. The fatty acid elongase Elovl6 is crucial for hematopoietic stem cell engraftment and leukemia propagation
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Yusuke Kiyoki, Takayasu Kato, Sakura Kito, Takashi Matsuzaka, Shin Morioka, Junko Sasaki, Kenichi Makishima, Tatsuhiro Sakamoto, Hidekazu Nishikii, Naoshi Obara, Mamiko Sakata-Yanagimoto, Takehiko Sasaki, Hitoshi Shimano, and Shigeru Chiba
- Subjects
Cancer Research ,Oncology ,Hematology - Published
- 2023
35. Hepatocyte- or macrophage-specific SREBP-1a deficiency in mice exacerbates methionine- and choline-deficient diet-induced nonalcoholic fatty liver disease
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Masaya Araki, Yoshimi Nakagawa, Hodaka Saito, Yasunari Yamada, Song-Iee Han, Yuhei Mizunoe, Hiroshi Ohno, Takafumi Miyamoto, Motohiro Sekiya, Takashi Matsuzaka, Hirohito Sone, and Hitoshi Shimano
- Subjects
Mice, Knockout ,Inflammation ,Hepatology ,Physiology ,Macrophages ,Gastroenterology ,Choline ,Diet ,Mice, Inbred C57BL ,Mice ,Methionine ,Liver ,Non-alcoholic Fatty Liver Disease ,Physiology (medical) ,Hepatocytes ,Animals ,Sterol Regulatory Element Binding Protein 1 - Abstract
Hepatocyte- and macrophage-specific SREBP-1a knockout mice were generated for the first time. This study reveals that SREBP-1a does not contribute to hepatic lipogenesis, but in either hepatocytes or macrophages distinctly controls the onset of pathological conditions in methionine- and choline-deficient diet-induced hepatitis.
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- 2022
36. Role of Fatty Acid Elongase Elovl6 in the Regulation of Fatty Acid Quality and Lifestyle-related Diseases
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Takashi, Matsuzaka and Hitoshi, Shimano
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Mice, Knockout ,Pharmacology ,Mice ,Diabetes Mellitus, Type 2 ,Acetyltransferases ,Fatty Acid Elongases ,Fatty Acids ,Animals ,Pharmaceutical Science ,Obesity ,Insulin Resistance ,Life Style - Abstract
The increasing prevalence of obesity worldwide has become an alarming public health concern because of dramatic increases in the incidence of obesity-associated diseases, including type 2 diabetes mellitus (T2DM). Peripheral insulin resistance and impaired insulin secretion remain the core defects in T2DM. Despite significant advances in unraveling the mechanisms underlying these defects, many of the metabolic pathways and regulators involved in insulin resistance and β-cell dysfunction are not completely understood. This review proposes that manipulating the fatty acid (FA) composition by blocking ELOVL fatty acid elongase 6 (Elovl6) could protect against insulin resistance, impaired insulin secretion, and obesity-related disorders. Elovl6 is a microsomal enzyme involved in the elongation of C16 saturated and monounsaturated FAs to form C18 FAs. We have reported that mice with Elovl6 deletion are protected against obesity-induced insulin resistance or β-cell failure because the cellular FA composition is changed, even with concurrent obesity. Therefore, Elovl6 appears to be a crucial metabolic checkpoint, and limiting the expression or activity of Elovl6 could be a new therapeutic approach in the treatment of T2DM.
- Published
- 2022
37. Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques
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Takahiro Nagatake, Shigenobu Kishino, Emiko Urano, Haruka Murakami, Nahoko Kitamura, Kana Konishi, Harumi Ohno, Prabha Tiwari, Sakiko Morimoto, Eri Node, Jun Adachi, Yuichi Abe, Junko Isoyama, Kento Sawane, Tetsuya Honda, Asuka Inoue, Akiharu Uwamizu, Takashi Matsuzaka, Yoichi Miyamoto, So-ichiro Hirata, Azusa Saika, Yuki Shibata, Koji Hosomi, Ayu Matsunaga, Hitoshi Shimano, Makoto Arita, Junken Aoki, Masahiro Oka, Akira Matsutani, Takeshi Tomonaga, Kenji Kabashima, Motohiko Miyachi, Yasuhiro Yasutomi, Jun Ogawa, and Jun Kunisawa
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Mice, Inbred C57BL ,PPAR gamma ,Macaca fascicularis ,Mice ,Adipose Tissue ,Macrophages ,Immunology ,Animals ,Immunology and Allergy ,Diet, High-Fat ,Lipids - Abstract
Dietary ω3 fatty acids have important health benefits and exert their potent bioactivity through conversion to lipid mediators. Here, we demonstrate that microbiota play an essential role in the body's use of dietary lipids for the control of inflammatory diseases. We found that amounts of 10-hydroxy-cis-12-cis-15-octadecadienoic acid (αHYA) and 10-oxo-cis-12-cis-15-octadecadienoic acid (αKetoA) increased in the feces and serum of specific-pathogen-free, but not germ-free, mice when they were maintained on a linseed oil diet, which is high in α-linolenic acid. Intake of αKetoA, but not αHYA, exerted anti-inflammatory properties through a peroxisome proliferator-activated receptor (PPAR)γ-dependent pathway and ameliorated hapten-induced contact hypersensitivity by inhibiting the development of inducible skin-associated lymphoid tissue through suppression of chemokine secretion from macrophages and inhibition of NF-κB activation in mice and cynomolgus macaques. Administering αKetoA also improved diabetic glucose intolerance by inhibiting adipose tissue inflammation and fibrosis through decreased macrophage infiltration in adipose tissues and altering macrophage M1/M2 polarization in mice fed a high-fat diet. These results collectively indicate that αKetoA is a novel postbiotic derived from α-linolenic acid, which controls macrophage-associated inflammatory diseases and may have potential for developing therapeutic drugs as well as probiotic food products.
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- 2022
38. Fatty acid elongation by ELOVL6 hampers remyelination by promoting inflammatory foam cell formation during demyelination.
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Corrales, Aida V. Garcia, Verberk, Sanne G. S., Haidar, Mansour, Grajchen, Elien, Dehairs, Jonas, Vanherle, Sam, Loix, Melanie, Weytjens, Tine, Gervois, Pascal, Takashi Matsuzaka, Lambrichts, Ivo, Swinnen, Johannes V., Bogie, Jeroen F. J., and Hendriks, Jerome J. A.
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FOAM cells ,FATTY acids ,MONOUNSATURATED fatty acids ,UNSATURATED fatty acids ,REMANUFACTURING ,DEMYELINATION - Abstract
A hallmark of multiple sclerosis (MS) is the formation of multiple focal demyelinating lesions within the central nervous system (CNS). These lesions mainly consist of phagocytes that play a key role in lesion progression and remyelination, and therefore represent a promising therapeutic target in MS. We recently showed that unsaturated fatty acids produced by stearoyl-CoA desaturase-1 induce inflammatory foam cell formation during demyelination. These fatty acids are elongated by the "elongation of very long chain fatty acids" proteins (ELOVLs), generating a series of functionally distinct lipids. Here, we show that the expression and activity of ELOVLs are altered in myelin-induced foam cells. Especially ELOVL6, an enzyme responsible for converting saturated and monounsaturated C16 fatty acids into C18 species, was found to be up-regulated in myelin phagocytosing phagocytes in vitro and in MS lesions. Depletion of Elovl6 induced a repair-promoting phagocyte phenotype through activation of the S1P/PPAR? pathway. Elovl6-deficient foamy macrophages showed enhanced ABCA1-mediated lipid efflux, increased production of neurotrophic factors, and reduced expression of inflammatory mediators. Moreover, our data show that ELOVL6 hampers CNS repair, as Elovl6 deficiency prevented demyelination and boosted remyelination in organotypic brain slice cultures and the mouse cuprizone model. These findings indicate that targeting ELOVL6 activity may be an effective strategy to stimulate CNS repair in MS and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]
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- 2023
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39. High protein diet-induced metabolic changes are transcriptionally regulated via KLF15-dependent and independent pathways
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Hitoshi Shimano, Akito Shikama, Yoshikazu Sawada, Chen Ye, Yoshihiko Izumida, Kyoka Katabami, Yoshinori Takeuchi, Man Hei Ho, Samia Karkoutly, Takehito Sugasawa, Kazuhiro Takekoshi, Zahra Mehrazad Saber, Takafumi Miyamoto, Duhan Tao, Yuki Murayama, Naoya Yahagi, Yuichi Aita, Yukari Masuda, Takashi Matsuzaka, and Yasushi Kawakami
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Male ,Transcription, Genetic ,medicine.medical_treatment ,Kruppel-Like Transcription Factors ,Biophysics ,KLF15 ,Biochemistry ,Mice ,Low-protein diet ,Genes, Reporter ,medicine ,Transcriptional regulation ,Animals ,Aspartate Aminotransferases ,Amino Acids ,Luciferases ,Molecular Biology ,Gene ,Transcription factor ,Mice, Knockout ,Zinc finger transcription factor ,chemistry.chemical_classification ,Sequence Analysis, RNA ,Chemistry ,Gene Expression Profiling ,Cystathionine gamma-Lyase ,Cell Biology ,Lipid Metabolism ,Adaptation, Physiological ,Amino acid ,Cell biology ,Mice, Inbred C57BL ,Metabolic pathway ,Glucose ,Gene Expression Regulation ,Liver ,Diet, High-Protein ,Female ,Signal Transduction - Abstract
High protein diet (HPD) is an affordable and positive approach in prevention and treatment of many diseases. It is believed that transcriptional regulation is responsible for adaptation after HPD feeding and Kruppel-like factor 15 (KLF15), a zinc finger transcription factor that has been proved to perform transcriptional regulation over amino acid, lipid and glucose metabolism, is known to be involved at least in part in this HPD response. To gain more insight into molecular mechanisms by which HPD controls expressions of genes involved in amino acid metabolism in the liver, we performed RNA-seq analysis of mice fed HPD for a short period (3 days). Compared to a low protein diet, HPD feeding significantly increased hepatic expressions of enzymes involved in the breakdown of all the 20 amino acids. Moreover, using KLF15 knockout mice and in vivo Ad-luc analytical system, we were able to identify Cth (cystathionine gamma-lyase) as a new target gene of KLF15 transcription as well as Ast (aspartate aminotransferase) as an example of KLF15-independent gene despite its remarkable responsiveness to HPD. These findings provide us with a clue to elucidate the entire transcriptional regulatory mechanisms of amino acid metabolic pathways.
- Published
- 2021
40. The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis
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Kouhei Tsumoto, Takehito Sugasawa, Shogo Nakano, Takatsugu Hirokawa, Ryunosuke Yoshino, Motohiro Sekiya, Takafumi Miyamoto, Hitoshi Shimano, Hiroaki Tokiwa, Kenta Kainoh, Satoru Nagatoishi, Yoshinori Takeuchi, and Takashi Matsuzaka
- Subjects
Science ,Primary Cell Culture ,Metabolic disorders ,Mice, Obese ,General Physics and Astronomy ,Cellular homeostasis ,Repressor ,Context (language use) ,FOXO1 ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,medicine ,Animals ,Homeostasis ,Humans ,Mice, Knockout ,Multidisciplinary ,Chemistry ,Lipogenesis ,Binding protein ,Gluconeogenesis ,Metabolic diseases ,General Chemistry ,medicine.disease ,Lipids ,Sterol regulatory element-binding protein ,Cell biology ,Fatty Liver ,Alcohol Oxidoreductases ,Disease Models, Animal ,Glucose ,Liver ,Steatohepatitis ,Co-Repressor Proteins ,Transcription - Abstract
Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches., Sensing of nutrient status coordinates the regulation of liver glucose and lipid metabolism, and is important for metabolic homeostasis. Here the authors report that transcriptional the corepressor CtBP2 can sense nutrient status and coordinate repression of liver glucose and lipid metabolism via Fox01 and SREBP1, respectively.
- Published
- 2021
41. Serum lactate dehydrogenase level as a possible predictor of treatment preference in psoriasis
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Yosuke Ishitsuka, Hitoshi Shimano, Yoshiyuki Nakamura, Naoko Okiyama, Takashi Matsuzaka, Hanako Koguchi-Yoshioka, Yasuhiro Fujisawa, Rei Watanabe, Junichi Furuta, Sae Inoue, Yutaka Matsumura, and Manabu Fujimoto
- Subjects
Adult ,Male ,Drug ,T-Lymphocytes ,media_common.quotation_subject ,Dermatology ,Disease ,Pharmacology ,Biochemistry ,Pathogenesis ,Oxygen Consumption ,Immune system ,Psoriasis ,Extracellular ,Humans ,Medicine ,Molecular Biology ,Aged ,media_common ,Aged, 80 and over ,L-Lactate Dehydrogenase ,business.industry ,Middle Aged ,medicine.disease ,Thalidomide ,Mechanism of action ,Case-Control Studies ,Female ,Phosphodiesterase 4 Inhibitors ,Apremilast ,medicine.symptom ,business ,medicine.drug - Abstract
Background The efficacy of small molecule inhibitors for intracellular signal mediators varies among the individuals, and their mechanism of action is broad. A phosphodiesterase 4 inhibitor apremilast shows a dramatic effect on a certain proportion of psoriatic patients by modulating the cellular metabolism and regulating the production of pro-inflammatory molecules. However, it is unclear to which disease subtype this drug benefits. While psoriasis is a Th17-mediated disease, how immune cells are affected by the modulation of cellular metabolism is not fully evaluated, either. Objective This study aims to identify the indices which predict the efficacy of apremilast in psoriasis, and to investigate the impact of metabolic activity in immune cells on the psoriatic pathogenesis. Methods The association of treatment efficacy with clinical and laboratory data of the 58 psoriatic patients was evaluated. The reflector of the associated index was also sought among the indices of cellular metabolic pathways by use of an extracellular flux analyzer. Results There was a correlation between clinical improvement and the serum lactate dehydrogenase (LDH) level in the patients treated with apremilast but not in those with biologics. Serum LDH level did not correlate with the cutaneous disease severity but correlated with the oxygen consumption rate of blood T cells. Conclusion Psoriatic patients with high serum LDH level can be benefitted by apremilast. The serum LDH level reflects the augmented respiratory activity of T cells in psoriasis. Our results would highlight the importance of regarding metabolic skew in immune cells as a treatment target in psoriasis.
- Published
- 2021
42. CtBP2 confers protection against oxidative stress through interactions with NRF1 and NRF2
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Hiroaki Suzuki, Hitoshi Shimano, Motohiro Sekiya, Yuki Murayama, Kenji Saito, Takafumi Miyamoto, Yoshinori Takeuchi, Yoko Sugano, Hitoshi Iwasaki, Ryo Takano, Naoya Yahagi, Takehito Sugasawa, Yoshimi Nakagawa, Kenta Kainoh, Yang Ma, Yoshinori Osaki, and Takashi Matsuzaka
- Subjects
0301 basic medicine ,Transcription, Genetic ,NF-E2-Related Factor 2 ,NF-E2-Related Factor 1 ,Biophysics ,Oxidative phosphorylation ,Biology ,medicine.disease_cause ,Biochemistry ,Antioxidants ,03 medical and health sciences ,0302 clinical medicine ,Transcriptional regulation ,medicine ,Humans ,Amino Acid Sequence ,NRF1 ,Molecular Biology ,Transcription factor ,Gene ,Obligate ,Binding protein ,Cell Biology ,Cell biology ,Alcohol Oxidoreductases ,Oxidative Stress ,030104 developmental biology ,Gene Expression Regulation ,030220 oncology & carcinogenesis ,Co-Repressor Proteins ,Oxidative stress ,Protein Binding - Abstract
While molecular oxygen is essential for aerobic organisms, its utilization is inseparably connected with generation of oxidative insults. To cope with the detrimental aspects, cells evolved antioxidative defense systems, and insufficient management of the oxidative insults underlies the pathogenesis of a wide range of diseases. A battery of genes for this antioxidative defense are regulated by the transcription factors nuclear factor-erythroid 2-like 1 and 2 (NRF1 and NRF2). While the regulatory steps for the activation of NRFs have been investigated with particular emphasis on nuclear translocation and proteosomal degradation, unknown redundancy may exist considering the indispensable nature of these defense systems. Here we unraveled that C-terminal binding protein 2 (CtBP2), a transcriptional cofactor with redox-sensing capability, is an obligate partner of NRFs. CtBP2 forms transcriptional complexes with NRF1 and NRF2 that is required to promote the expression of antioxidant genes in response to oxidative insults. Our findings illustrate a basis for understanding the transcriptional regulation of antioxidative defense systems that may be exploited therapeutically.
- Published
- 2021
43. Elongation of Long-Chain Fatty Acids Is Crucial for Hematopoietic Stem Cell Engraftment and Leukemia Propagation
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Takayasu Kato, Yusuke Kiyoki, Sakura Kito, Takashi Matsuzaka, Shin Morioka, Junko Sasaki, Tatsuhiro Sakamoto, Hidekazu Nishikii, Naoshi Obara, Mamiko Sakata-Yanagimoto, Takehiko Sasaki, Hitoshi Shimano, and Shigeru Chiba
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
44. ELOVL5-mediated fatty acid elongation promotes cellular proliferation and invasion in renal cell carcinoma
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Satoshi Nitta, Shuya Kandori, Ken Tanaka, Shotaro Sakka, Masanobu Siga, Yoshiyuki Nagumo, Hiromitsu Negoro, Takahiro Kojima, Bryan J. Mathis, Toru Shimazui, Takafumi Miyamoto, Takashi Matsuzaka, Hitoshi Shimano, and Hiroyuki Nishiyama
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Cancer Research ,Oncology ,Acetyltransferases ,Fatty Acid Elongases ,Fatty Acids ,Humans ,General Medicine ,Carcinoma, Renal Cell ,Proto-Oncogene Proteins c-akt ,Kidney Neoplasms ,Cell Proliferation - Abstract
Renal cell carcinoma (RCC) features altered lipid metabolism and accumulated polyunsaturated fatty acids (PUFAs). Elongation of very long-chain fatty acid (ELOVL) family enzymes catalyze fatty acid elongation, and ELOVL5 is indispensable for PUFAs elongation, but its role in RCC progression remains unclear. Here, we show that higher levels of ELOVL5 correlate with poor RCC clinical prognosis. Liquid chromatography/electrospray ionization-tandem mass spectrometry analysis showed decreases in ELOVL5 end products (arachidonic acid and eicosapentaenoic acid) under CRISPR/Cas9-mediated knockout of ELOVL5 while supplementation with these fatty acids partially reversed the cellular proliferation and invasion effects of ELOVL5 knockout. Regarding cellular proliferation and invasion, CRISPR/Cas9-mediated knockout of ELOVL5 suppressed the formation of lipid droplets and induced apoptosis via endoplasmic reticulum stress while suppressing renal cancer cell proliferation and in vivo tumor growth. Furthermore, CRISPR/Cas9-mediated knockout of ELOVL5 inhibited AKT Ser473 phosphorylation and suppressed renal cancer cell invasion through chemokine (C-C motif) ligand-2 downregulation by AKT-mTOR-STAT3 signaling. Collectively, these results suggest that ELOVL5-mediated fatty acid elongation promotes not only cellular proliferation but also invasion in RCC.
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- 2022
45. Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition
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Yoshinori Osaki, Hirohito Sone, Yuki Murayama, Masaya Araki, Yoshimi Nakagawa, Hitoshi Shimano, Nobuyuki Itoh, Takashi Matsuzaka, Yuhei Mizunoe, Asayo Oishi, Yuka Yagishita, Hiroshi Ohno, Nobuhiro Yamada, Morichika Konishi, Yunong Wang, Song-iee Han, Hitoshi Iwasaki, Kae Kumagai, and Kanako Okuda
- Subjects
0301 basic medicine ,Lipoprotein lipase ,FGF21 ,Hepatology ,Cholesterol ,Endoplasmic reticulum ,Gastroenterology ,CREB3L3 ,ER retention ,SREBP ,Sterol regulatory element-binding protein ,Cell biology ,03 medical and health sciences ,chemistry.chemical_compound ,Hyperlipidemia ,030104 developmental biology ,0302 clinical medicine ,chemistry ,Enterohepatic Circulation ,lcsh:Diseases of the digestive system. Gastroenterology ,lipids (amino acids, peptides, and proteins) ,030211 gastroenterology & hepatology ,lcsh:RC799-869 ,Transcription factor ,Lipoprotein - Abstract
Background & Aims cAMP responsive element-binding protein 3 like 3 (CREB3L3) is a membrane-bound transcription factor involved in the maintenance of lipid metabolism in the liver and small intestine. CREB3L3 controls hepatic triglyceride and glucose metabolism by activating plasma fibroblast growth factor 21 (FGF21) and lipoprotein lipase. In this study, we intended to clarify its effect on atherosclerosis. Methods CREB3L3-deficifient, liver-specific CREB3L3 knockout, intestine-specific CREB3L3 knockout, both liver- and intestine-specific CREB3L3 knockout, and liver CREB3L3 transgenic mice were crossed with LDLR−/− mice. These mice were fed with a Western diet to develop atherosclerosis. Results CREB3L3 ablation in LDLR−/− mice exacerbated hyperlipidemia with accumulation of remnant APOB-containing lipoprotein. This led to the development of enhanced aortic atheroma formation, the extent of which was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly up-regulates anti-atherogenic FGF21 and APOA4. In contrast, it antagonizes hepatic sterol regulatory element-binding protein (SREBP)–mediated lipogenic and cholesterogenic genes and regulates intestinal liver X receptor–regulated genes involved in the transport of cholesterol. CREB3L3 deficiency results in the accumulation of nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs in the endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 promotes the formation of the SREBP-insulin induced gene 1 complex to suppress SREBPs for ER-Golgi transport, resulting in ER retention and inhibition of proteolytic activation at the Golgi and vice versa. Conclusions CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions.
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- 2021
46. Oxidative stress and Liver X Receptor agonist induce hepatocellular carcinoma in Non‐alcoholic steatohepatitis model
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Nobuhiro Ohkohchi, Takashi Matsuzaka, Yoshio Shimizu, Shingo Sakashita, Katsuji Hisakura, Hitoshi Shimano, Noriyuki Nakano, Tatsuya Oda, Akira Kemmochi, Yusuke Ozawa, Takafumi Tamura, and Yohei Owada
- Subjects
Male ,Agonist ,medicine.medical_specialty ,Carcinoma, Hepatocellular ,Hydrocarbons, Fluorinated ,medicine.drug_class ,Experimental Hepatology ,CCL4 ,Diet, High-Fat ,medicine.disease_cause ,digestive system ,03 medical and health sciences ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Internal medicine ,parasitic diseases ,Animals ,Medicine ,Liver X receptor ,Carbon Tetrachloride ,Non‐alcoholic steatohepatitis ,Liver X Receptors ,Sulfonamides ,Hepatology ,business.industry ,Liver Neoplasms ,Gastroenterology ,Lipid metabolism ,Lipid Metabolism ,medicine.disease ,digestive system diseases ,Mice, Inbred C57BL ,NASH‐related HCC ,Disease Models, Animal ,Oxidative Stress ,Endocrinology ,Liver ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Disease Progression ,030211 gastroenterology & hepatology ,Steatohepatitis ,Steatosis ,business ,Injections, Intraperitoneal ,Oxidative stress ,Regular Articles - Abstract
Background and Aim The incidence of non‐alcoholic steatohepatitis (NASH)‐related hepatocellular carcinoma (HCC) is progressively increasing. However, the pathophysiology and etiology of NASH progression to HCC are unknown. We hypothesized that steatosis was the key factor in NASH‐related hepatocarcinogenesis and aimed to evaluate the effects of long‐term liver X receptor (LXR) agonist stimulation on hepatic steatosis induced by a high‐fat diet and oxidative stress. Methods We used an LXR agonist (T0901317) and CCl4 to induce hepatic steatosis and oxidative stress, respectively. C57BL/6 mice fed with a high‐fat diet were treated with either T0901317 + CCl4 (T09 + CCl4 group) or CCl4 alone (CCl4 group). T0901317 (2.5 mg/kg) and CCl4 (0.1 mL/kg) were intraperitoneally administered twice weekly for 24 weeks. Results The liver‐to‐body weight ratio was significantly higher in the T09 + CCl4 group than in the CCl4 group. Mice in the T09 + CCl4 group exhibited abnormal lipid metabolism and NASH‐like histopathological features. Additionally, all mice in the T09 + CCl4 group developed liver tumors diagnosed as well‐differentiated HCC. The genes identified via microarray analysis were related to NASH and HCC development. Conclusions By combining long‐term LXR agonist stimulation with oxidative stress and a high‐fat diet, we successfully reproduced liver conditions in mice similar to those in humans with NASH and progression to HCC. Our results provide new insight into NASH‐related HCC progression and therapy.
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- 2020
47. Identification of Key MicroRNAs Regulating ELOVL6 and Glioblastoma Tumorigenesis
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Nurani Istiqamah, Takashi Matsuzaka, Kaori Motomura, Hiroshi Ohno, Shiho Hasebe, Rahul Sharma, Yuka Okajima, Erika Matsuda, Song-Iee Han, Yuhei Mizunoe, Yoshinori Osaki, Yuichi Aita, Hiroaki Suzuki, Hirohito Sone, Yoshinori Takeuchi, Motohiro Sekiya, Naoya Yahagi, Yoshimi Nakagawa, and Hitoshi Shimano
- Subjects
History ,Polymers and Plastics ,Business and International Management ,Industrial and Manufacturing Engineering - Published
- 2022
48. Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids
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Takashi Matsuzaka, Tadashi Imafuku, Soken Tsuchiya, Masafumi Fukagawa, Hitoshi Maeda, Takehiro Nakano, Shoma Tanaka, Takao Satoh, Hitoshi Shimano, Toru Maruyama, Naomi Nakagata, Hiromasa Kato, Yuka Nakamura, Tomoaki Inazumi, Motoko Tanaka, Hiroshi Watanabe, Ayumi Mukunoki, Yukihiko Sugimoto, Kazutaka Matsushita, Kai Tokumaru, and Toru Takeo
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medicine.medical_specialty ,Fatty Acid Elongases ,Original Investigations ,Inflammation ,mTORC1 ,030204 cardiovascular system & hematology ,Kidney ,Nephrotoxicity ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Tubulopathy ,Acetyltransferases ,Internal medicine ,medicine ,Animals ,030304 developmental biology ,0303 health sciences ,Reabsorption ,business.industry ,Fatty Acids ,Albumin ,General Medicine ,medicine.disease ,Endocrinology ,Advanced Oxidation Protein Products ,Unfolded protein response ,medicine.symptom ,business ,Kidney disease - Abstract
BACKGROUND: Renal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy. METHODS: Mice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies. RESULTS: In kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway. CONCLUSIONS: AOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.
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- 2020
49. Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl‐Chain Length and Hepatic Insulin Sensitivity in Mice
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Yuta Yamamoto, Saori Koyasu, Motoko Kuba, Yuichi Aita, Yuka Okajima, Kaori Motomura, Naoya Yahagi, Satoru Takahashi, Rahul Sharma, Yoshinori Osaki, Shigeru Yatoh, Hiroaki Suzuki, Yuhei Mizunoe, Hitoshi Iwasaki, Takuya Shimura, Hitoshi Shimano, Yoshimi Nakagawa, Yoshinori Takeuchi, Sundaram Arulmozhiraja, Song-iee Han, Masatsugu Ema, Hiroaki Tokiwa, Takashi Matsuzaka, Takafumi Miyamoto, Motohiro Sekiya, Hiroshi Ohno, and Hirohito Sone
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Ceramide ,Fatty Acid Elongases ,Down-Regulation ,Ceramides ,Liver disorder ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Insulin resistance ,Dietary Sucrose ,Non-alcoholic Fatty Liver Disease ,Lipid droplet ,Internal medicine ,Sphingosine N-Acyltransferase ,Nonalcoholic fatty liver disease ,medicine ,Animals ,Protein Phosphatase 2 ,Protein kinase B ,Mice, Knockout ,Hepatology ,biology ,medicine.disease ,Insulin receptor ,030104 developmental biology ,Endocrinology ,Liver ,chemistry ,Phospholipases A2, Calcium-Independent ,Lipogenesis ,biology.protein ,030211 gastroenterology & hepatology ,Insulin Resistance - Abstract
Background and aims Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity-induced insulin resistance by modifying hepatic C16/C18-related FA composition. Approach and results To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver-specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high-fat diet-induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high-sucrose diet (HSD), which induces lipogenesis. Hepatic patatin-like phospholipase domain-containing protein 3 (Pnpla3) expression was down-regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD-fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1/18:0) enhances protein phosphatase 2A (PP2A) activity by interfering with the binding of PP2A to inhibitor 2 of PP2A, leading to Akt dephosphorylation. Its production involves the formation of an Elovl6-ceramide synthase 4 (CerS4) complex in the endoplasmic reticulum and a Pnpla3-CerS4 complex on lipid droplets. Consistent with this, liver-specific Elovl6 deletion in ob/ob mice reduced both hepatic ceramide(d18:1/18:0) and PP2A activity and ameliorated insulin resistance. Conclusions Our study demonstrates the key role of hepatic Elovl6 in the regulation of the acyl-chain composition of ceramide and that C18:0-ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3-mediated NAFLD.
- Published
- 2020
50. Predictive ability of current machine learning algorithms for type 2 diabetes mellitus: A meta-analysis
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Satoru Kodama, Kazuya Fujihara, Chika Horikawa, Masaru Kitazawa, Midori Iwanaga, Kiminori Kato, Kenichi Watanabe, Yoshimi Nakagawa, Takashi Matsuzaka, Hitoshi Shimano, and Hirohito Sone
- Subjects
Machine Learning ,Diabetes Mellitus, Type 2 ,ROC Curve ,Endocrinology, Diabetes and Metabolism ,Internal Medicine ,Humans ,General Medicine ,Algorithms ,Forecasting - Abstract
Recently, an increasing number of cohort studies have suggested using machine learning (ML) to predict type 2 diabetes mellitus. However, its predictive ability remains inconclusive. This meta-analysis evaluated the current ability of ML algorithms for predicting incident type 2 diabetes mellitus.We systematically searched longitudinal studies published from 1 January 1950 to 17 May 2020 using MEDLINE and EMBASE. Included studies had to compare ML's classification with the actual incidence of type 2 diabetes mellitus, and present data on the number of true positives, false positives, true negatives and false negatives. The dataset for these four values was pooled with a hierarchical summary receiver operating characteristic and a bivariate random effects model.There were 12 eligible studies. The pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio were 0.81 (95% confidence interval [CI] 0.67-0.90), 0.82 [95% CI 0.74-0.88], 4.55 [95% CI 3.07-6.75] and 0.23 [95% CI 0.13-0.42], respectively. The area under the summarized receiver operating characteristic curve was 0.88 (95% CI 0.85-0.91).Current ML algorithms have sufficient ability to help clinicians determine whether individuals will develop type 2 diabetes mellitus in the future. However, persons should be cautious before changing their attitude toward future diabetes risk after learning the result of the diabetes prediction test using ML algorithms.
- Published
- 2021
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