31 results on '"Greenberg, Andrew S."'
Search Results
2. NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice.
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Fotio, Yannick, Mabou Tagne, Alex, Squire, Erica, Lee, Hye-lim, Phillips, Connor M., Chang, Kayla, Ahmed, Faizy, Greenberg, Andrew S., Villalta, S. Armando, Scarfone, Vanessa M., Spadoni, Gilberto, Mor, Marco, and Piomelli, Daniele
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HYPERALGESIA ,PEROXISOME proliferator-activated receptors ,CHRONIC pain ,MICE ,MONOCYTES ,LIPIDS ,LABORATORY mice - Abstract
Circulating monocytes participate in pain chronification but the molecular events that cause their deployment are unclear. Using a mouse model of hyperalgesic priming (HP), we show that monocytes enable progression to pain chronicity through a mechanism that requires transient activation of the hydrolase, N-acylethanolamine acid amidase (NAAA), and the consequent suppression of NAAA-regulated lipid signaling at peroxisome proliferator-activated receptor-α (PPAR-α). Inhibiting NAAA in the 72 hours following administration of a priming stimulus prevented HP. This effect was phenocopied by NAAA deletion and depended on PPAR-α recruitment. Mice lacking NAAA in CD11b
+ cells – monocytes, macrophages, and neutrophils – were resistant to HP induction. Conversely, mice overexpressing NAAA or lacking PPAR-α in the same cells were constitutively primed. Depletion of monocytes, but not resident macrophages, generated mice that were refractory to HP. The results identify NAAA-regulated signaling in monocytes as a control node in the induction of HP and, potentially, the transition to pain chronicity. Circulating monocytes contribute to the transition to pain chronicity but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming, here the authors show that blood monocytes contribute to the emergence of chronic pain via a mechanism that requires a transient disruption of NAAA-regulated lipid signaling. [ABSTRACT FROM AUTHOR]- Published
- 2024
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3. A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction
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Killion, Elizabeth A., Reeves, Andrew R., El Azzouny, Mahmoud A., Yan, Qing-Wu, Surujon, Defne, Griffin, John D., Bowman, Thomas A., Wang, Chunyan, Matthan, Nirupa R., Klett, Eric L., Kong, Dong, Newman, John W., Han, Xianlin, Lee, Mi-Jeong, Coleman, Rosalind A., and Greenberg, Andrew S.
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- 2018
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4. Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption
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Bowman, Thomas A., O'Keeffe, Kayleigh R., D'Aquila, Theresa, Yan, Qing Wu, Griffin, John D., Killion, Elizabeth A., Salter, Deanna M., Mashek, Douglas G., Buhman, Kimberly K., and Greenberg, Andrew S.
- Published
- 2016
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5. The Impacts of Slc19a3 Deletion and Intestinal SLC19A3 Insertion on Thiamine Distribution and Brain Metabolism in the Mouse.
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Wen, Anita, Zhu, Ying, Yee, Sook Wah, Park, Brian I., Giacomini, Kathleen M., Greenberg, Andrew S., and Newman, John W.
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VITAMIN B1 ,BRAIN metabolism ,THIAMIN pyrophosphate ,AMINO acid derivatives ,ERYTHROCYTES ,HEART ,INTESTINES - Abstract
The Thiamine Transporter 2 (THTR2) encoded by SLC19A3 plays an ill-defined role in the maintenance of tissue thiamine, thiamine monophosphate, and thiamine diphosphate (TDP) levels. To evaluate the impact of THTR2 on tissue thiamine status and metabolism, we expressed the human SLC19A3 transgene in the intestine of total body Slc19a3 knockout (KO) mice. Male and female wildtype (WT) and transgenic (TG) mice were fed either 17 mg/kg (1×) or 85 mg/kg (5×) thiamine hydrochloride diet, while KOs were only fed the 5× diet. Thiamine vitamers in plasma, red blood cells, duodenum, brain, liver, kidney, heart, and adipose tissue were measured. Untargeted metabolomics were performed on the brain tissues of groups with equivalent plasma thiamine. KO mice had ~two- and ~three-fold lower plasma and brain thiamine levels than WT on the 5× diet. Circulating vitamers were sensitive to diet and equivalent in TG and WT mice. However, TG had 60% lower thiamine but normal brain TDP levels regardless of diet, with subtle differences in the heart and liver. The loss of THTR2 reduced levels of nucleic acid and amino acid derivatives in the brain. Therefore, mutation or inhibition of THTR2 may alter the brain metabolome and reduce the thiamine reservoir for TDP biosynthesis. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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6. The good and bad of adipose tissue macrophage exosomes in obesity
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Greenberg, Andrew S. and Reeves, Andrew R.
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- 2021
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7. Tissue-Specific Ablation of ACSL4 Results in Disturbed Steroidogenesis.
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Wang, Wei, Hao, Xiao, Han, Lina, Yan, Zhe, Shen, Wen-Jun, Dong, Dachuan, Hasbargen, Kathrin, Bittner, Stefanie, Cortez, Yuan, Greenberg, Andrew S, Azhar, Salman, and Kraemer, Fredric B
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- 2019
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8. Inhibition of diethylnitrosamine-initiated alcohol-promoted hepatic inflammation and precancerous lesions by flavonoid luteolin is associated with increased sirtuin 1 activity in mice
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Rafacho, Bruna Paola Murino, Stice, Camilla Peach, Liu, Chun, Greenberg, Andrew S., Ausman, Lynne M., and Wang, Xiang-Dong
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Original Article - Abstract
Chronic and excessive alcohol consumption is an established risk for hepatic inflammation and carcinogenesis. Luteolin is one of the most common flavonoids present in plants and has potential beneficial effects against cancer. In this study, we examined the effect and potential mechanisms of luteolin supplementation in a carcinogen initiated alcohol-promoted pre-neoplastic liver lesion mouse model.C57BL/6 mice were injected with diethylnitrosamine (DEN) [i.p. 25 mg/kg of body weight (BW)] at 14 days of age. At 8 weeks of age mice were group pair-fed with Lieber-DeCarli liquid control diet or alcoholic diet [ethanol (EtOH) diet, 27% total energy from ethanol] and supplemented with a dose of 30 mg luteolin/kg BW per day for 21 days.DEN-injected mice fed EtOH diet displayed a significant induction of pre-neoplastic lesions, a marker associated with presence of steatosis and inflammation. Dietary luteolin significantly reduced the severity and incidence of hepatic inflammatory foci and steatosis in DEN-injected mice fed EtOH diet, as well the presence of preneoplastic lesions. There was no difference on hepatic protein levels of sirtuin 1 (SIRT1) among all groups; however, luteolin supplementation significantly reversed alcohol-reduced SIRT1 activity assessed by the ratio of acetylated and total forkhead box protein O1 (FoXO1) and SIRT1 target proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α).Dietary intake of luteolin prevents alcohol promoted pre-neoplastic lesions, potentially mediated by SIRT1 signaling pathway.
- Published
- 2015
9. Dorsal Plating for Intra-articular Middle Phalangeal Base Fractures With Volar Instability.
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Doering, Travis A., Greenberg, Andrew S., and Tuckman, David V.
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Background: Intra-articular middle phalangeal base fractures with volar instability are rare injuries with scant literature on optimal management. Our purpose is to describe our method of dorsal plating and report postoperative outcomes. Methods: This study is a retrospective case review of 5 patients with intra-articular middle phalangeal base fractures with volar proximal interphalangeal joint instability, measuring subjective, clinical, and radiographic outcomes. Results: Patient age averaged 38.2 years (range, 23-56 years), and 80% were male. Sporting injuries were the most common mechanism (80%). Time to surgery averaged 7 days, and postoperative follow-up duration averaged 19.6 months (median 8 months). All fractures were intra-articular at the proximal interphalangeal joint with volar instability. There were no complications and no patients required secondary surgery. Grip strength was maintained and range of motion was good, based on the American Society for Surgery of the Hand Total Active Motion score. Average Quick Disability of the Arm, Shoulder and Hand was 0.5 (range, 0-2.3), 100% of patients were satisfied, and average visual analog pain score was 1.2. Patients returned to work at a median of 4 days. There was radiographic union at an average of 6.6 weeks (range, 6-7 weeks) in all fractures. Conclusions: Dorsal plating using a 1.5-mm modular hand plate is a viable option for rigid fixation of intra-articular middle phalangeal base fractures with volar instability. This fixation method allows for early range of motion without complications in this case series. All fractures united, and patients had minimal functional deficits and were able to maintain good range of motion. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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10. The data of change in macrophage gene expression which induced by perilipin 1 overexpression
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Yamamoto, Kohei, Miyoshi, Hideaki, Cho, Kyu Yong, Nakamura, Akinobu, Greenberg, Andrew S., and Atsumi, Tatsuya
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- 2018
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11. Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A.
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Kazutaka Ueda, Eiki Takimoto, Qing Lu, Pangyen Liu, Nobuaki Fukuma, Yusuke Adachi, Ryo Suzuki, Shengpu Chou, Baur, Wendy, Aronovitz, Mark J., Greenberg, Andrew S., Issei Komuro, Karas, Richard H., Ueda, Kazutaka, Takimoto, Eiki, Lu, Qing, Liu, Pangyen, Fukuma, Nobuaki, Adachi, Yusuke, and Suzuki, Ryo
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ESTROGEN receptors ,CELLULAR signal transduction ,METABOLIC disorders ,HOMEOSTASIS ,WEIGHT gain ,DIABETES risk factors ,GLUCOSE intolerance - Abstract
Women gain weight and their diabetes risk increases as they transition through menopause; these changes can be partly reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen receptor (ER) pathway was used, and we found that the lack of this pathway precipitated excessive weight gain and glucose intolerance independent of food intake and that this was accompanied by impaired adaptive thermogenesis and reduced physical activity. Notably, the central activation of protein phosphatase (PP) 2A improved metabolic disorders induced by the lack of membrane-initiated ER signaling. Furthermore, the antiobesity effect of estrogen replacement in a murine menopause model was abolished by central PP2A inactivation. These findings define a critical role for membrane-initiated ER signaling in metabolic homeostasis via the central action of PP2A. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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12. CDK6 inhibits white to beige fat transition by suppressing RUNX1.
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Xiaoli Hou, Yongzhao Zhang, Wei Li, Hu, Alexander J., Chi Luo, Wenhui Zhou, Hu, Jamie K., Daniele, Stefano G., Jinfeng Wang, Jinghao Sheng, Yongsheng Fan, Greenberg, Andrew S., Farmer, Stephen R., and Hu, Miaofen G.
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WHITE adipose tissue ,BROWN adipose tissue ,PROTEIN kinases ,METABOLIC disorders ,INSULIN resistance - Abstract
Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6
-/- mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1α by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases. [ABSTRACT FROM AUTHOR]- Published
- 2018
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13. Gender Disparity in the Relationship between Prevalence of Thyroid Nodules and Metabolic Syndrome Components: The SHDC-CDPC Community-Based Study.
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Ding, Xiaoying, Xu, Ying, Wang, Yufan, Li, Xiaohua, Lu, Chunhua, Su, Jing, Chen, Yuting, Ma, Yuhang, Yin, Yanhua, Wu, Yong, Jin, Yaqiong, Yu, Lihua, Jiang, Junyi, Zhao, Naisi, Yan, Qingwu, Greenberg, Andrew S., Sun, Haiyan, Gu, Mingyu, Zhao, Li, and Huang, Yunhong
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SEX discrimination in medicine ,DISEASE prevalence ,METABOLIC syndrome ,THYROID diseases ,HYPERURICEMIA - Abstract
The study is aimed to investigate the pathogenesis underlying the increased prevalence of thyroid nodule (TN) in different levels of metabolic syndrome (MetS) components and analyze the relationships between TN and MetS components. A total of 6,798 subjects, including 2201 patients with TN, were enrolled in this study. Anthropometric, biochemical, thyroid ultrasonographic, and other metabolic parameters were all measured. There was obviously sexual difference in the prevalence of TN (males 26.0%, females 38.5%, resp.). The prevalence of TN in hyperuricemia (45.7% versus 37.4%, P = 0.001), NAFLD (41.2% versus 36.4%, P < 0.05), and MetS (41.4% versus 35.4%, P < 0.001) groups was significantly increased only in females. Insulin resistance [OR = 1.31 (1.15, 1.49)], MetS [OR = 1.18 (1.03, 1.35)], and diabetes [OR = 1.25 (1.06, 1.48)] were all independent risk factors for TN in total subjects, whereas, after stratified analysis of gender, MetS [OR = 1.29, (1.09, 1.53)] and diabetes [OR = 1.47, (1.17, 1.84)] are still strongly and independently associated with the higher risks of TN in female subjects, but not in males. Our results suggest that the components of MetS might associate with the higher risks of TN in women than in men, but further cohort study of this gender disparity in the association between TN and MetS is required. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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14. Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome.
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Rui Liu, Chenhong Zhang, Yu Shi, Feng Zhang, Linxia Li, Xuejiao Wang, Yunxia Ling, Huaqing Fu, Weiping Dong, Jian Shen, Reeves, Andrew, Greenberg, Andrew S., Liping Zhao, Yongde Peng, and Xiaoying Ding
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POLYCYSTIC ovary syndrome ,OVARIAN cysts ,GUT microbiome - Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. Gut microbiota has been implicated to play a critical role in metabolic diseases and may modulate the secretion of mediators of the brain-gut axis. Interaction between gut microbiota and the endocrine and biochemical disturbances in PCOS still remains elusive. Here, we showed an altered gut microbiota significantly correlated with PCOS phenotype. There were 33 patients with PCOS (non-obese PCOS individuals, PN, n = 12; obese PCOS individuals, PO, n = 21) as well as 15 control subjects (non-obese control individuals, CN, n = 9; obese control individuals, CO, n = 6) enrolled in our study. The plasma levels of serotonin, ghrelin, and peptide YY (PYY) were significantly decreased in patients with PCOS compared with controls, and have a significantly negative correlation with waist circumference and testosterone. Sequencing of the V3-V4 region of the 16S rRNA gene in fecal samples revealed the substantial differences of gut microbial species between the PCOS and non-obese controls. Bacterial species were clustered into 23 co-abundance groups (CAGs) based on the SparCC correlation coefficients of their relative abundance. The CAGs increased in PCOS, including the bacteria belonging to Bacteroides, Escherichia/Shigella and Streptococcus, were negatively correlated with ghrelin, and positively correlated with testosterone and BMI. Furthermore, the CAGs that were decreased in PCOS, including the bacteria from Akkermansia and Ruminococcaceae, showed opposite relationship with body-weight, sex-hormone, and brain-gut peptides. In conclusion, gut microbial dysbiosis in women with PCOS is associated with the disease phenotypes. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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15. Tissue Concentrations of Vitamin K and Expression of Key Enzymes of Vitamin K Metabolism Are Influenced by Sex and Diet but Not Housing in C57Bl6 Mice.
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Harshman, Stephanie G., Xueyan Fu, Karl, J. Philip, Barger, Kathryn, Lamon-Fava, Stefania, Kuliopulos, Athan, Greenberg, Andrew S., Smith, Donald, Xiaohua Shen, Booth, Sarah L., Fu, Xueyan, and Shen, Xiaohua
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VITAMIN K ,VITAMIN metabolism ,GENE expression ,VITAMIN K2 ,HIGH performance liquid chromatography ,ADIPOSE tissues ,VITAMIN K epoxide reductase ,LABORATORY mice ,BRAIN metabolism ,ANIMAL experimentation ,VITAMIN deficiency ,DIET ,HOUSING ,KIDNEYS ,LIVER ,MEMBRANE proteins ,MESENTERY ,MICE ,OXIDOREDUCTASES ,PANCREAS ,RESEARCH funding ,SEX distribution ,TRANSFERASES - Abstract
Background: There has been limited characterization of biological variables that impact vitamin K metabolism. This gap in knowledge can limit the translation of data obtained from preclinical animal studies to future human studies.Objective: The purpose of this study was to determine the effects of diet, sex, and housing on serum, tissue, and fecal vitamin K concentrations and gene expression in C57BL6 mice during dietary vitamin K manipulation.Methods: C57BL6 4-mo-old male and female mice were randomly assigned to conventional or suspended-wire cages and fed control [1400 ± 80 μg phylloquinone (PK)/kg] or deficient (31 ± 0.45 μg PK/kg) diets for 28 d in a factorial design. PK and menaquinone (MK) 4 plasma and tissue concentrations were measured by HPLC. Long-chain MKs were measured in all matrices by LC-atmospheric pressure chemical ionization-mass spectrometry. Gene expression was quantified by reverse transcriptase-polymerase chain reaction in the liver, brain, kidney, pancreas, and adipose tissue.Results: Male and female mice responded differently to dietary manipulation in a tissue-dependent manner. In mice fed the control diet, females had ∼3-fold more MK4 in the brain and mesenteric adipose tissue than did males and 100% greater PK concentrations in the liver, kidney, and mesenteric adipose tissue than did males. In mice fed the deficient diet, kidney MK4 concentrations were ∼4-fold greater in females than in males, and there were no differences in other tissues. Males and females differed in the expression of vitamin K expoxide reductase complex 1 (Vkorc1) in mesenteric adipose tissue and the pancreas and ubiA domain-containing protein 1 (Ubiad1) in the kidney and brain. There was no effect of housing on serum, tissue, or fecal concentrations of any vitamin K form.Conclusions: Vitamin K concentrations and expression of key metabolic enzymes differ between male and female mice and in response to the dietary PK concentration. Identifying factors that may impact study design and outcomes of interest is critical to optimize study parameters examining vitamin K metabolism in animal models. [ABSTRACT FROM AUTHOR]- Published
- 2016
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16. Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice.
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Xinli Li, Chun Liu, Ip, Blanche C., Kang-Quan Hu, Smith, Donald E., Greenberg, Andrew S., and Xiang-Dong Wang
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CANCER invasiveness ,LOCUS (Genetics) ,LIVER cancer ,FATTY degeneration ,LABORATORY mice ,KNOCKOUT mice ,GENETICS - Abstract
Background: Tumor progression locus 2 (TPL2), a serine-threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unknown. Methods: Both wild-type and Tpl2 knockout male mice were initiated by a hepatic carcinogen (diethylnitrosamine, i.p. with a single dose of 25 mg.kg
-1 )at 2 weeks of age, and then were given the high carbohydrate diet feeding to induce hepatic steatosis, inflammation, adenoma and HCC for 24 weeks. Results: Tpl2 knockout mice had significantly lower incidences of liver tumor and developed hepatocellular adenoma only, which is contrast to wild-type mice where they all developed HCC. Tpl2 knockout mice had significantly downregulated phosphorylation of JNK and ERK, and levels of mRNA expression of pro-inflammatory cytokines (Il-1β, Il-18, Mcp-1 and Nalp3), which correlated with the reduced incidence and number of hepatic inflammatory foci. Furthermore, Tpl2 ablation resulted in decreased hepatic steatosis and expression of de novo lipogenesis related markers (ACC, SCD1, SREBP1C and AKT phosphorylation), as well as reduction of endoplasmic reticulum stress biomarkers PERK and eIF-2a. Conclusion: The study revealed for the first time that Tpl2 plays a significant role in promoting HCC development by its pro-inflammatory effect, which suggested that Tpl2 could be a molecular target for HCC prevention. [ABSTRACT FROM AUTHOR]- Published
- 2015
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17. Diet- and Genetically-Induced Obesity Differentially Affect the Fecal Microbiome and Metabolome in Apc1638N Mice.
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Pfalzer, Anna C., Nesbeth, Paula-Dene C., Parnell, Laurence D., Iyer, Lakshmanan K., Liu, Zhenhua, Kane, Anne V., Chen, C-Y. Oliver, Tai, Albert K., Bowman, Thomas A., Obin, Martin S., Mason, Joel B., Greenberg, Andrew S., Choi, Sang-Woon, Selhub, Jacob, Paul, Ligi, and Crott, Jimmy W.
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DIETARY supplements ,MICROBIOLOGY ,FECES ,METABOLOMICS ,LABORATORY mice ,COLON cancer risk factors ,OBESITY - Abstract
Obesity is a risk factor for colorectal cancer (CRC), and alterations in the colonic microbiome and metabolome may be mechanistically involved in this relationship. The relative contribution of diet and obesity per se are unclear. We compared the effect of diet- and genetically-induced obesity on the intestinal microbiome and metabolome in a mouse model of CRC. Apc
1638N mice were made obese by either high fat (HF) feeding or the presence of the Leprdb/db (DbDb) mutation. Intestinal tumors were quantified and stool microbiome and metabolome were profiled. Genetic obesity, and to a lesser extent HF feeding, promoted intestinal tumorigenesis. Each induced distinct microbial patterns: taxa enriched in HF were mostly Firmicutes (6 of 8) while those enriched in DbDb were split between Firmicutes (7 of 12) and Proteobacteria (5 of 12). Parabecteroides distasonis was lower in tumor-bearing mice and its abundance was inversely associated with colonic Il1b production (p<0.05). HF and genetic obesity altered the abundance of 49 and 40 fecal metabolites respectively, with 5 in common. Of these 5, adenosine was also lower in obese and in tumor-bearing mice (p<0.05) and its concentration was inversely associated with colonic Il1b and Tnf production (p<0.05). HF and genetic obesity differentially alter the intestinal microbiome and metabolome. A depletion of adenosine and P.distasonis in tumor-bearing mice could play a mechanistic role in tumor formation. Adenosine and P. distasonis have previously been shown to be anti-inflammatory in the colon and we postulate their reduction could promote tumorigenesis by de-repressing inflammation. [ABSTRACT FROM AUTHOR]- Published
- 2015
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18. Characterization of the Proteome of Cytoplasmic Lipid Droplets in Mouse Enterocytes after a Dietary Fat Challenge.
- Author
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D’Aquila, Theresa, Sirohi, Devika, Grabowski, Jeffrey M., Hedrick, Victoria E., Paul, Lake N., Greenberg, Andrew S., Kuhn, Richard J., and Buhman, Kimberly K.
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CYTOPLASM ,ENTEROCYTES ,FAT content of food ,LABORATORY mice ,DIETARY supplements - Abstract
Dietary fat absorption by the small intestine is a multistep process that regulates the uptake and delivery of essential nutrients and energy. One step of this process is the temporary storage of dietary fat in cytoplasmic lipid droplets (CLDs). The storage and mobilization of dietary fat is thought to be regulated by proteins that associate with the CLD; however, mechanistic details of this process are currently unknown. In this study we analyzed the proteome of CLDs isolated from enterocytes harvested from the small intestine of mice following a dietary fat challenge. In this analysis we identified 181 proteins associated with the CLD fraction, of which 37 are associated with known lipid related metabolic pathways. We confirmed the localization of several of these proteins on or around the CLD through confocal and electron microscopy, including perilipin 3, apolipoprotein A-IV, and acyl-CoA synthetase long-chain family member 5. The identification of the enterocyte CLD proteome provides new insight into potential regulators of CLD metabolism and the process of dietary fat absorption. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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19. Integrated Action of Autophagy and Adipose Tissue Triglyceride Lipase Ameliorates Diet-Induced Hepatic Steatosis in Liver-Specific PLIN2 Knockout Mice.
- Author
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Griffin, John D., Bejarano, Eloy, Wang, Xiang-Dong, Greenberg, Andrew S., Canbay, Ali, and Combaret, Lydie
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FATTY liver ,NON-alcoholic fatty liver disease ,PERILIPIN ,KNOCKOUT mice ,LIPOLYSIS ,AUTOPHAGY ,ADIPOSE tissues - Abstract
An imbalance in the storage and breakdown of hepatic lipid droplet (LD) triglyceride (TAG) leads to hepatic steatosis, a defining feature of non-alcoholic fatty liver disease (NAFLD). The two primary cellular pathways regulating hepatic TAG catabolism are lipolysis, initiated by adipose triglyceride lipase (ATGL), and lipophagy. Each of these processes requires access to the LD surface to initiate LD TAG catabolism. Ablation of perilipin 2 (PLIN2), the most abundant lipid droplet-associated protein in steatotic liver, protects mice from diet-induced NAFLD. However, the mechanisms underlaying this protection are unclear. We tested the contributions of ATGL and lipophagy mediated lipolysis to reduced hepatic TAG in mice with liver-specific PLIN2 deficiency (PLIN2
LKO ) fed a Western-type diet for 12 weeks. We observed enhanced autophagy in the absence of PLIN2, as determined by ex vivo p62 flux, as well as increased p62- and LC3-positive autophagic vesicles in PLIN2LKO livers and isolated primary hepatocytes. Increased levels of autophagy correlated with significant increases in cellular fatty acid (FA) oxidation in PLIN2LKO hepatocytes. We observed that inhibition of either autophagy or ATGL blunted the increased FA oxidation in PLIN2LKO hepatocytes. Additionally, combined inhibition of ATGL and autophagy reduced FA oxidation to the same extent as treatment with either inhibitor alone. In sum, these studies show that protection against NAFLD in the absence of hepatic PLIN2 is driven by the integrated actions of both ATGL and lipophagy. [ABSTRACT FROM AUTHOR]- Published
- 2021
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20. Decellularized extracellular matrix scaffolds identify full-length collagen VI as a driver of breast cancer cell invasion in obesity and metastasis.
- Author
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Wishart, Andrew L., Conner, Sydney J., Guarin, Justinne R., Fatherree, Jackson P., Yifan Peng, McGinn, Rachel A., Crews, Rebecca, Naber, Stephen P., Hunter, Martin, Greenberg, Andrew S., and Oudin, Madeleine J.
- Subjects
- *
EXTRACELLULAR matrix , *CANCER cells , *COLLAGEN , *CELL receptors , *BREAST cancer , *TRANSFORMING growth factors , *INTEGRINS - Abstract
The article discusses the extracellular matrix (ECM), a major component of the tumor microenvironment, promotes local invasion to drive metastasis. Topics include a method to study whole-tissue ECM effects from disease states associated with metastasis on tumor cell phenotypes and identify the individual ECM proteins; and triple-negative breast cancer, representing 15 to 20% of breast cancer cases, has aggressive.
- Published
- 2020
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21. Lipid Droplet Protein PLIN1 Regulates Inflammatory Polarity in Human Macrophages and is Involved in Atherosclerotic Plaque Development by Promoting Stable Lipid Storage.
- Author
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Cho KY, Miyoshi H, Nakamura A, Greenberg AS, and Atsumi T
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- Humans, Lipid Droplets metabolism, Leukocytes, Mononuclear metabolism, Macrophages metabolism, Perilipin-2 genetics, Perilipin-2 metabolism, Lipids, RNA metabolism, Perilipin-1 genetics, Perilipin-1 metabolism, Plaque, Atherosclerotic metabolism
- Abstract
Aim: Perilipins (PLINs), peripheral lipid droplet (LD) proteins, play important roles in lipid accumulation and maturation in adipocytes. The relationship between PLIN family proteins and macrophage polarization in atherosclerosis has not been elucidated., Methods: The experiments used tissues from human arteries of 65 patients who had undergone a carotid endarterectomy, and cultured macrophages generated from healthy human peripheral blood mononuclear cells., Results: Plaque immunohistochemistry demonstrated co-expression of PLIN1 and PLIN2 in both symptomatic (n=31) and asymptomatic patients (n=34). PLIN2 mRNA expression increased 3.38-fold in the symptomatic group compared with those from asymptomatic. PLIN1 was not expressed on small LDs at a shorter incubation but was on large LDs at longer incubation with oxidized LDL and VLDL, while PLIN2 was observed after 24 h and increased with a longer incubation in cultured M1 macrophage. In M2 macrophages, PLIN1 was seen as early as 24 h following incubation with VLDL, and LD size increased with longer incubation. PLIN1 overexpression increased the size of LDs in M1 macrophages, even after a short incubation, and reduced the RNA expression of TNFA, MMP2, ABCA1, and ABCG1 versus the M1 control. Conversely, silencing of PLIN1 in M2 macrophages had the opposite effects on LD size and RNA expression., Conclusion: There was a relationship between macrophage polarity, cytosolic LD size, and PLIN1/PLIN2 expression levels. PLIN2 was mainly expressed in arterial plaques in symptomatic stroke patients, and associated with the inflammatory phenotype of human macrophages, while PLIN1 expression is closely associated with plaque stability and the anti-inflammatory phenotype.
- Published
- 2023
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22. Perilipin 2 downregulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria.
- Author
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Mishra A, Liu S, Promes J, Harata M, Sivitz W, Fink B, Bhardwaj G, O'Neill BT, Kang C, Sah R, Strack S, Stephens S, King T, Jackson L, Greenberg AS, Anokye-Danso F, Ahima RS, Ankrum J, and Imai Y
- Subjects
- Animals, Carnitine analogs & derivatives, Carnitine metabolism, Diet, High-Fat, Down-Regulation, Glucose metabolism, Humans, In Vitro Techniques, Islets of Langerhans, Mice, Mice, Knockout, Mitochondria metabolism, Oleic Acid metabolism, Oxidative Phosphorylation, Oxidative Stress genetics, Oxygen Consumption genetics, Perilipin-2 metabolism, Rats, Insulin Secretion genetics, Insulin-Secreting Cells metabolism, Lipid Droplets metabolism, Perilipin-2 genetics, Stress, Physiological genetics
- Abstract
Perilipin 2 (PLIN2) is a lipid droplet (LD) protein in β cells that increases under nutritional stress. Downregulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects β cell function under nutritional stress, PLIN2 was downregulated in mouse β cells, INS1 cells, and human islet cells. β Cell-specific deletion of PLIN2 in mice on a high-fat diet reduced glucose-stimulated insulin secretion (GSIS) in vivo and in vitro. Downregulation of PLIN2 in INS1 cells blunted GSIS after 24-hour incubation with 0.2 mM palmitic acid. Downregulation of PLIN2 in human pseudoislets cultured at 5.6 mM glucose impaired both phases of GSIS, indicating that PLIN2 is critical for GSIS. Downregulation of PLIN2 decreased specific OXPHOS proteins in all 3 models and reduced oxygen consumption rates in INS1 cells and mouse islets. Moreover, we found that PLIN2-deficient INS1 cells increased the distribution of a fluorescent oleic acid analog to mitochondria and showed signs of mitochondrial stress, as indicated by susceptibility to fragmentation and alterations of acyl-carnitines and glucose metabolites. Collectively, PLIN2 in β cells has an important role in preserving insulin secretion, β cell metabolism, and mitochondrial function under nutritional stress.
- Published
- 2021
- Full Text
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23. Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A.
- Author
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Ueda K, Takimoto E, Lu Q, Liu P, Fukuma N, Adachi Y, Suzuki R, Chou S, Baur W, Aronovitz MJ, Greenberg AS, Komuro I, and Karas RH
- Subjects
- 3T3-L1 Cells, Adipocytes drug effects, Adipocytes metabolism, Adipocytes pathology, Adiposity drug effects, Amino Acid Substitution, Animals, Cells, Cultured, Diet, High-Fat adverse effects, Enzyme Activation drug effects, Estradiol pharmacology, Estradiol therapeutic use, Estrogen Receptor alpha genetics, Estrogen Receptor alpha metabolism, Female, Gene Knock-In Techniques, Glucose Intolerance etiology, Glucose Intolerance metabolism, Glucose Intolerance pathology, Insulin Resistance, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Smooth, Vascular drug effects, Muscle, Smooth, Vascular metabolism, Muscle, Smooth, Vascular pathology, Obesity etiology, Obesity metabolism, Obesity pathology, Ovariectomy, Point Mutation, Protein Phosphatase 2 chemistry, Estrogen Receptor alpha agonists, Estrogen Replacement Therapy, Glucose Intolerance prevention & control, Menopause, Obesity prevention & control, Protein Phosphatase 2 metabolism, Signal Transduction drug effects
- Abstract
Women gain weight and their diabetes risk increases as they transition through menopause; these changes can be partly reversed by hormone therapy. However, the underlying molecular mechanisms mediating these effects are unknown. A novel knock-in mouse line with the selective blockade of the membrane-initiated estrogen receptor (ER) pathway was used, and we found that the lack of this pathway precipitated excessive weight gain and glucose intolerance independent of food intake and that this was accompanied by impaired adaptive thermogenesis and reduced physical activity. Notably, the central activation of protein phosphatase (PP) 2A improved metabolic disorders induced by the lack of membrane-initiated ER signaling. Furthermore, the antiobesity effect of estrogen replacement in a murine menopause model was abolished by central PP2A inactivation. These findings define a critical role for membrane-initiated ER signaling in metabolic homeostasis via the central action of PP2A., (© 2018 by the American Diabetes Association.)
- Published
- 2018
- Full Text
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24. CDK6 inhibits white to beige fat transition by suppressing RUNX1.
- Author
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Hou X, Zhang Y, Li W, Hu AJ, Luo C, Zhou W, Hu JK, Daniele SG, Wang J, Sheng J, Fan Y, Greenberg AS, Farmer SR, and Hu MG
- Subjects
- Adipocytes cytology, Animals, Body Composition, Cell Differentiation, Core Binding Factor Alpha 2 Subunit genetics, Core Binding Factor Alpha 2 Subunit metabolism, Crosses, Genetic, Cyclin-Dependent Kinase 6 genetics, Diet, High-Fat, Female, Gene Expression Profiling, Glucose Tolerance Test, Male, Metabolic Diseases metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity genetics, Obesity metabolism, Oxygen Consumption, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha metabolism, Phenotype, Uncoupling Protein 1 metabolism, Adipose Tissue, Brown physiology, Adipose Tissue, White physiology, Core Binding Factor Alpha 2 Subunit antagonists & inhibitors, Cyclin-Dependent Kinase 6 metabolism, Gene Expression Regulation
- Abstract
Whereas white adipose tissue depots contribute to the development of metabolic diseases, brown and beige adipose tissue has beneficial metabolic effects. Here we show that CDK6 regulates beige adipocyte formation. We demonstrate that mice lacking the CDK6 protein or its kinase domain (K43M) exhibit significant increases beige cell formation, enhanced energy expenditure, better glucose tolerance, and improved insulin sensitivity, and are more resistant to high-fat diet-induced obesity. Re-expression of CDK6 in Cdk6
-/- mature or precursor cells, or ablation of RUNX1 in K43M mature or precursor cells, reverses these phenotypes. Furthermore, RUNX1 positively regulates the expression of Ucp-1 and Pgc1α by binding to proximal promoter regions. Our findings indicate that CDK6 kinase activity negatively regulates the conversion of fat-storing cells into fat-burning cells by suppressing RUNX1, and suggest that CDK6 may be a therapeutic target for the treatment of obesity and related metabolic diseases.- Published
- 2018
- Full Text
- View/download PDF
25. Dysbiosis of Gut Microbiota Associated with Clinical Parameters in Polycystic Ovary Syndrome.
- Author
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Liu R, Zhang C, Shi Y, Zhang F, Li L, Wang X, Ling Y, Fu H, Dong W, Shen J, Reeves A, Greenberg AS, Zhao L, Peng Y, and Ding X
- Abstract
Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disorder in women. Gut microbiota has been implicated to play a critical role in metabolic diseases and may modulate the secretion of mediators of the brain-gut axis. Interaction between gut microbiota and the endocrine and biochemical disturbances in PCOS still remains elusive. Here, we showed an altered gut microbiota significantly correlated with PCOS phenotype. There were 33 patients with PCOS (non-obese PCOS individuals, PN, n = 12; obese PCOS individuals, PO, n = 21) as well as 15 control subjects (non-obese control individuals, CN, n = 9; obese control individuals, CO, n = 6) enrolled in our study. The plasma levels of serotonin, ghrelin, and peptide YY (PYY) were significantly decreased in patients with PCOS compared with controls, and have a significantly negative correlation with waist circumference and testosterone. Sequencing of the V3-V4 region of the 16S rRNA gene in fecal samples revealed the substantial differences of gut microbial species between the PCOS and non-obese controls. Bacterial species were clustered into 23 co-abundance groups (CAGs) based on the SparCC correlation coefficients of their relative abundance. The CAGs increased in PCOS, including the bacteria belonging to Bacteroides, Escherichia/Shigella and Streptococcus , were negatively correlated with ghrelin, and positively correlated with testosterone and BMI. Furthermore, the CAGs that were decreased in PCOS, including the bacteria from Akkermansia and Ruminococcaceae, showed opposite relationship with body-weight, sex-hormone, and brain-gut peptides. In conclusion, gut microbial dysbiosis in women with PCOS is associated with the disease phenotypes.
- Published
- 2017
- Full Text
- View/download PDF
26. Nonalcoholic Fatty Liver Disease and Associated Metabolic Risks of Hypertension in Type 2 Diabetes: A Cross-Sectional Community-Based Study.
- Author
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Ding X, Xu Y, Wang Y, Li X, Lu C, Su J, Ma Y, Chen Y, Yin Y, Zhang L, Wu Y, Jin Y, Zheng L, Xu S, Zhu X, Ma J, Yu L, Jiang J, Zhao N, Yan Q, Greenberg AS, Huang Q, Ren Q, Sun H, Gu M, Zhao L, Huang Y, Wu Y, Qian C, and Peng Y
- Abstract
The mechanisms facilitating hypertension in diabetes still remain to be elucidated. Nonalcoholic fatty liver disease (NAFLD), which is a higher risk factor for insulin resistance, shares many predisposing factors with diabetes. However, little work has been performed on the pathogenesis of hypertension in type 2 diabetes (T2DM) with NAFLD. The aim of this study is to investigate the prevalence of hypertension in different glycemic statuses and to analyze relationships between NAFLD, metabolic risks, and hypertension within a large community-based population after informed written consent. A total of 9473 subjects aged over 45 years, including 1648 patients with T2DM, were enrolled in this cross-sectional study. Clinical and biochemical parameters of all participants were determined. The results suggested that the patients with prediabetes or T2DM were with higher risks to have hypertension. T2DM with NAFLD had significantly higher levels of blood pressure, triglyceride, uric acid, and HOMA-IR than those without NAFLD. Data analyses suggested that hypertriglyceridemia [OR = 1.773 (1.396, 2.251)], NAFLD [OR = 2.344 (1.736, 3.165)], hyperuricemia [OR = 1.474 (1.079, 2.012)], and insulin resistance [OR = 1.948 (1.540, 2.465)] were associated with the higher prevalence of hypertension independent of other metabolic risk factors in type 2 diabetes. Further studies are needed to focus on these associations.
- Published
- 2017
- Full Text
- View/download PDF
27. Deletion of tumor progression locus 2 attenuates alcohol-induced hepatic inflammation.
- Author
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Stice CP, Hussain S, Liu C, Ausman LM, Wang XD, and Greenberg AS
- Abstract
Background: The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine-threonine kinase that functions as a critical regulator of inflammatory pathways by up-regulating production of inflammatory cytokines. The present study aims to fill the gap in knowledge regarding the involvement of TPL2 in the mechanism of alcohol-induced hepatic inflammation., Methods: Male TPL2(-/-) knockout (TPL2KO) mice and TPL2(+/+) wild-type (WT) mice were group pair-fed with Lieber-DeCarli liquid ethanol diet (EtOH diet, 27% energy from EtOH) or control diet (ctrl diet) for 4 weeks. Both histological and molecular biomarkers involved in the induction of hepatic inflammation by alcohol consumption were examined., Results: Consumption of the EtOH diet in WT mice lead to a significant induction of TPL2 mRNA expression as compared with WT mice fed ctrl diet. A significant induction in inflammatory foci and steatosis was also observed in WT mice fed EtOH diet. The deletion of TPL2 significantly reduced inflammatory foci in the liver of mice consuming both ctrl and EtOH diets as compared to their respective WT controls. This reduction was associated with suppression of hepatic inflammatory gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) and macrophage marker F4/80. In addition, histological analysis of livers revealed that TPL2 deletion resulted in reduced steatosis in both ctrl (significant) and EtOH (non-significant) diet-fed mice as compared to their respective WT controls., Conclusions: The demonstration that TPL2 deletion attenuates alcohol-induced hepatic inflammation provides evidence of a novel role for TPL2 in the pathogenesis of ALD.
- Published
- 2016
- Full Text
- View/download PDF
28. Tumor progression locus 2 ablation suppressed hepatocellular carcinoma development by inhibiting hepatic inflammation and steatosis in mice.
- Author
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Li X, Liu C, Ip BC, Hu KQ, Smith DE, Greenberg AS, and Wang XD
- Subjects
- Animals, Body Weight genetics, Carcinoma, Hepatocellular metabolism, Cell Transformation, Neoplastic genetics, Disease Models, Animal, Endoplasmic Reticulum Stress genetics, Fatty Liver metabolism, Gene Expression Regulation, Hepatitis metabolism, Humans, Lipogenesis genetics, Liver Neoplasms metabolism, MAP Kinase Signaling System, Mice, Mice, Knockout, Organ Size genetics, Carcinoma, Hepatocellular etiology, Fatty Liver complications, Fatty Liver genetics, Hepatitis complications, Hepatitis genetics, Liver Neoplasms etiology, MAP Kinase Kinase Kinases genetics, Proto-Oncogene Proteins genetics
- Abstract
Background: Tumor progression locus 2 (TPL2), a serine-threonine kinase, functions as a critical regulator of inflammatory pathways and mediates oncogenic events. The potential role of Tpl2 in nonalcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) development remains unknown., Methods: Both wild-type and Tpl2 knockout male mice were initiated by a hepatic carcinogen (diethylnitrosamine, i.p. with a single dose of 25 mg.kg(-1))at 2 weeks of age, and then were given the high carbohydrate diet feeding to induce hepatic steatosis, inflammation, adenoma and HCC for 24 weeks., Results: Tpl2 knockout mice had significantly lower incidences of liver tumor and developed hepatocellular adenoma only, which is contrast to wild-type mice where they all developed HCC. Tpl2 knockout mice had significantly down-regulated phosphorylation of JNK and ERK, and levels of mRNA expression of pro-inflammatory cytokines (Il-1β, Il-18, Mcp-1 and Nalp3), which correlated with the reduced incidence and number of hepatic inflammatory foci. Furthermore, Tpl2 ablation resulted in decreased hepatic steatosis and expression of de novo lipogenesis related markers (ACC, SCD1, SREBP1C and AKT phosphorylation), as well as reduction of endoplasmic reticulum stress biomarkers PERK and eIF-2a., Conclusion: The study revealed for the first time that Tpl2 plays a significant role in promoting HCC development by its pro-inflammatory effect, which suggested that Tpl2 could be a molecular target for HCC prevention.
- Published
- 2015
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- View/download PDF
29. Diet- and Genetically-Induced Obesity Differentially Affect the Fecal Microbiome and Metabolome in Apc1638N Mice.
- Author
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Pfalzer AC, Nesbeth PD, Parnell LD, Iyer LK, Liu Z, Kane AV, Chen CY, Tai AK, Bowman TA, Obin MS, Mason JB, Greenberg AS, Choi SW, Selhub J, Paul L, and Crott JW
- Subjects
- Animals, Female, Intestinal Neoplasms genetics, Intestinal Neoplasms metabolism, Intestinal Neoplasms microbiology, Male, Mice, Mutation, Obesity etiology, Obesity metabolism, Obesity microbiology, Receptors, Leptin deficiency, Diet, High-Fat adverse effects, Feces chemistry, Feces microbiology, Metabolome drug effects, Metabolome genetics, Microbiota drug effects, Microbiota genetics, Obesity genetics, Receptors, Leptin genetics
- Abstract
Obesity is a risk factor for colorectal cancer (CRC), and alterations in the colonic microbiome and metabolome may be mechanistically involved in this relationship. The relative contribution of diet and obesity per se are unclear. We compared the effect of diet- and genetically-induced obesity on the intestinal microbiome and metabolome in a mouse model of CRC. Apc1638N mice were made obese by either high fat (HF) feeding or the presence of the Leprdb/db (DbDb) mutation. Intestinal tumors were quantified and stool microbiome and metabolome were profiled. Genetic obesity, and to a lesser extent HF feeding, promoted intestinal tumorigenesis. Each induced distinct microbial patterns: taxa enriched in HF were mostly Firmicutes (6 of 8) while those enriched in DbDb were split between Firmicutes (7 of 12) and Proteobacteria (5 of 12). Parabecteroides distasonis was lower in tumor-bearing mice and its abundance was inversely associated with colonic Il1b production (p<0.05). HF and genetic obesity altered the abundance of 49 and 40 fecal metabolites respectively, with 5 in common. Of these 5, adenosine was also lower in obese and in tumor-bearing mice (p<0.05) and its concentration was inversely associated with colonic Il1b and Tnf production (p<0.05). HF and genetic obesity differentially alter the intestinal microbiome and metabolome. A depletion of adenosine and P.distasonis in tumor-bearing mice could play a mechanistic role in tumor formation. Adenosine and P. distasonis have previously been shown to be anti-inflammatory in the colon and we postulate their reduction could promote tumorigenesis by de-repressing inflammation.
- Published
- 2015
- Full Text
- View/download PDF
30. Characterization of the proteome of cytoplasmic lipid droplets in mouse enterocytes after a dietary fat challenge.
- Author
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D'Aquila T, Sirohi D, Grabowski JM, Hedrick VE, Paul LN, Greenberg AS, Kuhn RJ, and Buhman KK
- Subjects
- Animals, Apolipoproteins A metabolism, Carrier Proteins metabolism, Coenzyme A Ligases metabolism, Enterocytes ultrastructure, Lipid Droplets ultrastructure, Lipid Metabolism, Male, Metabolic Networks and Pathways, Mice, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Models, Biological, Perilipin-3, Triglycerides metabolism, Dietary Fats administration & dosage, Enterocytes metabolism, Lipid Droplets metabolism, Proteome metabolism
- Abstract
Dietary fat absorption by the small intestine is a multistep process that regulates the uptake and delivery of essential nutrients and energy. One step of this process is the temporary storage of dietary fat in cytoplasmic lipid droplets (CLDs). The storage and mobilization of dietary fat is thought to be regulated by proteins that associate with the CLD; however, mechanistic details of this process are currently unknown. In this study we analyzed the proteome of CLDs isolated from enterocytes harvested from the small intestine of mice following a dietary fat challenge. In this analysis we identified 181 proteins associated with the CLD fraction, of which 37 are associated with known lipid related metabolic pathways. We confirmed the localization of several of these proteins on or around the CLD through confocal and electron microscopy, including perilipin 3, apolipoprotein A-IV, and acyl-CoA synthetase long-chain family member 5. The identification of the enterocyte CLD proteome provides new insight into potential regulators of CLD metabolism and the process of dietary fat absorption.
- Published
- 2015
- Full Text
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31. Inhibition of diethylnitrosamine-initiated alcohol-promoted hepatic inflammation and precancerous lesions by flavonoid luteolin is associated with increased sirtuin 1 activity in mice.
- Author
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Rafacho BP, Stice CP, Liu C, Greenberg AS, Ausman LM, and Wang XD
- Abstract
Background: Chronic and excessive alcohol consumption is an established risk for hepatic inflammation and carcinogenesis. Luteolin is one of the most common flavonoids present in plants and has potential beneficial effects against cancer. In this study, we examined the effect and potential mechanisms of luteolin supplementation in a carcinogen initiated alcohol-promoted pre-neoplastic liver lesion mouse model., Methods: C57BL/6 mice were injected with diethylnitrosamine (DEN) [i.p. 25 mg/kg of body weight (BW)] at 14 days of age. At 8 weeks of age mice were group pair-fed with Lieber-DeCarli liquid control diet or alcoholic diet [ethanol (EtOH) diet, 27% total energy from ethanol] and supplemented with a dose of 30 mg luteolin/kg BW per day for 21 days., Results: DEN-injected mice fed EtOH diet displayed a significant induction of pre-neoplastic lesions, a marker associated with presence of steatosis and inflammation. Dietary luteolin significantly reduced the severity and incidence of hepatic inflammatory foci and steatosis in DEN-injected mice fed EtOH diet, as well the presence of preneoplastic lesions. There was no difference on hepatic protein levels of sirtuin 1 (SIRT1) among all groups; however, luteolin supplementation significantly reversed alcohol-reduced SIRT1 activity assessed by the ratio of acetylated and total forkhead box protein O1 (FoXO1) and SIRT1 target proliferator-activated receptor gamma, coactivator 1 alpha (PGC1α)., Conclusions: Dietary intake of luteolin prevents alcohol promoted pre-neoplastic lesions, potentially mediated by SIRT1 signaling pathway.
- Published
- 2015
- Full Text
- View/download PDF
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