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1. Sanguisorba officinalis L. Ameliorates Hepatic Steatosis and Fibrosis by Modulating Oxidative Stress, Fatty Acid Oxidation, and Gut Microbiota in CDAHFD-Induced Mice.

Author

Nam, Yunseong, Kim, Myungsuk, Erdenebileg, Saruul, Cha, Kwang Hyun, Ryu, Da Hye, Kim, Ho Youn, Lee, Su Hyeon, Jung, Je Hyeong, and Nho, Chu Won

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver diseases and encompasses non-alcoholic steatosis, steatohepatitis, and fibrosis. Sanguisorba officinalis L. (SO) roots have traditionally been used for their antioxidant properties and have beneficial effects on metabolic disorders, including diabetes and obesity. However, its effects on hepatic steatosis and fibrosis remain unclear. In this study, we explored the effects of a 95% ethanolic SO extract (SOEE) on NAFLD and fibrosis in vivo and in vitro. The SOEE was orally administered to C57BL/6J mice fed a choline-deficient, L-amino-acid-defined, high-fat diet for 10 weeks. The SOEE inhibited hepatic steatosis by modulating hepatic malondialdehyde levels and the expression of oxidative stress-associated genes, regulating fatty-acid-oxidation-related genes, and inhibiting the expression of genes that are responsible for fibrosis. The SOEE suppressed the deposition of extracellular matrix hydroxyproline and mRNA expression of fibrosis-associated genes. The SOEE decreased the expression of fibrosis-related genes in vitro by inhibiting SMAD2/3 phosphorylation. Furthermore, the SOEE restored the gut microbial diversity and modulated specific bacterial genera associated with NAFLD and fibrosis. This study suggests that SOEE might be the potential candidate for inhibiting hepatic steatosis and fibrosis by modulating oxidative stress, fatty acid oxidation, and gut microbiota composition. [ABSTRACT FROM AUTHOR]

Published
2023
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2. TWEAK/Fn14 Signalling Regulates the Tissue Microenvironment in Chronic Pancreatitis.

Author

Abu Bakar, N. Dianah B., Carlessi, Rodrigo, Gogoi-Tiwari, Jully, Köhn-Gaone, Julia, Williams, Vincent, Falasca, Marco, Olynyk, John K., Ramm, Grant A., and Tirnitz-Parker, Janina E. E.

Subjects
*BIOLOGICAL models, *CHRONIC diseases, *CARCINOGENESIS, *ANIMAL experimentation, *IMMUNOLOGIC receptors, *CELLULAR signal transduction, *GENE expression, *TUMOR necrosis factors, *PANCREATITIS, *MICE, *DISEASE complications
Abstract

Simple Summary: The TWEAK/Fn14 signalling pathway has emerged as a major regulator of tissue injury and regeneration through its pro-proliferative, pro-inflammatory, and pro-fibrotic cellular effects. Its role in pancreatic injury and cancer has not been elucidated. In this study, we confirmed the choline-deficient, ethionine-supplemented diet as a suitable murine model to study chronic pancreatitis and demonstrated that TWEAK/Fn14 signalling plays a significant role in the establishment and progression of the chronic pancreatitis tissue microenvironment. Chronic pancreatitis increases the risk of developing pancreatic cancer through the upregulation of pathways favouring proliferation, fibrosis, and sustained inflammation. We established in previous studies that the ligand tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signals through its cognate receptor fibroblast growth factor-inducible 14 (Fn14) to regulate these underlying cellular processes in the chronic liver injury niche. However, the role of the TWEAK/Fn14 signalling pathway in pancreatic disease is entirely unknown. An analysis of publicly available datasets demonstrated that the TWEAK receptor Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, with single cell RNA sequencing revealing pancreatic ductal cells as the main Fn14 producers. We then used choline-deficient, ethionine-supplemented (CDE) diet feeding of wildtype C57BL/6J and Fn14 knockout littermates to (a) confirm CDE treatment as a suitable model of chronic pancreatitis and (b) to investigate the role of the TWEAK/Fn14 signalling pathway in pancreatic ductal proliferation, as well as fibrotic and inflammatory cell dynamics. Our time course data obtained at three days, three months, and six months of CDE treatment reveal that a lack of TWEAK/Fn14 signalling significantly inhibits the establishment and progression of the tissue microenvironment in CDE-induced chronic pancreatitis, thus proposing the TWEAK/Fn14 pathway as a novel therapeutic target. [ABSTRACT FROM AUTHOR]

Published
2023
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3. A trans fatty acid substitute enhanced development of liver proliferative lesions induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet

Author

Noriko Suzuki-Kemuriyama, Akari Abe, Kiniko Uno, Shuji Ogawa, Atsushi Watanabe, Ryuhei Sano, Megumi Yuki, Katsuhiro Miyajima, and Dai Nakae

Subjects
Nonalcoholic steatohepatitis, Trans fatty acid substitutes, Choline-deficient, Methionine-lowered, L-amino acid-defined, High-fat diet, Nutritional diseases. Deficiency diseases, RC620-627
Abstract

Abstract Background Nonalcoholic steatohepatitis (NASH) is a form of liver disease characterized by steatosis, necroinflammation, and fibrosis, resulting in cirrhosis and cancer. Efforts have focused on reducing the intake of trans fatty acids (TFAs) because of potential hazards to human health and the increased risk for NASH. However, the health benefits of reducing dietary TFAs have not been fully elucidated. Here, the effects of TFAs vs. a substitute on NASH induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet (CDAA-HF) were investigated. Methods Mice were fed CDAA-HF containing shortening with TFAs (CDAA-HF-T(+)), CDAA-HF containing shortening without TFAs (CDAA-HF-T(−)), or a control chow for 13 or 26 weeks. Results At week 13, NASH was induced in mice by feeding CDAA-HF-T(+) containing TFAs or CDAA-HF-T(−) containing no TFAs, but rather mostly saturated fatty acids (FAs), as evidenced by elevated serum transaminase activity and liver changes, including steatosis, inflammation, and fibrosis. CDAA-HF-T(−) induced a greater extent of hepatocellular apoptosis at week 13. At week 26, proliferative (preneoplastic and non-neoplastic) nodular lesions were more pronounced in mice fed CDAA-HF-T(−) than CDAA-HF-T(+). Conclusions Replacement of dietary TFAs with a substitute promoted the development of proliferation lesions in the liver of a mouse NASH model, at least under the present conditions. Attention should be paid regarding use of TFA substitutes in foods for human consumption, and a balance of FAs is likely more important than the particular types of FAs.

Published
2020
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4. Assessment of hepatic fatty acids during non-alcoholic steatohepatitis progression using magnetic resonance spectroscopy.

Author

Xavier, Aline, Zacconi, Flavia, Santana-Romo, Fabián, Eykyn, Thomas R., Lavin, Begoña, Phinikaridou, Alkystis, Botnar, René, Uribe, Sergio, Oyarzún, Juan Esteban, Cabrera, Daniel, Arrese, Marco, and Andia, Marcelo E.

Subjects
FATTY liver, NUCLEAR magnetic resonance spectroscopy, NON-alcoholic fatty liver disease, FATTY acids, GAS chromatography/Mass spectrometry (GC-MS), DISEASE progression
Abstract

Introduction and objectives: Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver abnormalities including steatosis, steatohepatitis, fibrosis, and cirrhosis. Liver biopsy remains the gold standard method to determine the disease stage in NAFLD but is an invasive and risky procedure. Studies have previously reported that changes in intrahepatic fatty acids (FA) composition are related to the progression of NAFLD, mainly in its early stages. The aim of this study was to characterize the liver FA composition in mice fed a Choline-deficient L-amino-defined (CDAA) diet at different stages of NAFLD using magnetic resonance spectroscopy (MRS). Methods: We used in-vivo MRS to perform a longitudinal characterization of hepatic FA changes in NAFLD mice for 10 weeks. We validated our findings with ex-vivo MRS, gas chromatography-mass spectrometry and histology. Results: In-vivo and ex-vivo results showed that livers from CDAA-fed mice exhibit a significant increase in liver FA content as well as a change in FA composition compared with control mice. After 4 weeks of CDAA diet, a decrease in polyunsaturated and an increase in monounsaturated FA were observed. These changes were associated with the appearance of early stages of steatohepatitis, confirmed by histology (NAFLD Activity Score (NAS) = 4.5). After 10 weeks of CDAA-diet, the liver FA composition remained stable while the NAS increased further to 6 showing a combination of early and late stages of steatohepatitis. Conclusion: Our results suggest that monitoring lipid composition in addition to total water/fat with MRS may yield additional insights that can be translated for non-invasive stratification of high-risk NAFLD patients. [ABSTRACT FROM AUTHOR]

Published
2021
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5. A trans fatty acid substitute enhanced development of liver proliferative lesions induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet.

Author

Suzuki-Kemuriyama, Noriko, Abe, Akari, Uno, Kiniko, Ogawa, Shuji, Watanabe, Atsushi, Sano, Ryuhei, Yuki, Megumi, Miyajima, Katsuhiro, and Nakae, Dai

Subjects
*TRANS fatty acids, *CHOLINE, *HIGH-fat diet, *MICE, *LIVER, *CONSUMPTION (Economics)
Abstract

Background: Nonalcoholic steatohepatitis (NASH) is a form of liver disease characterized by steatosis, necroinflammation, and fibrosis, resulting in cirrhosis and cancer. Efforts have focused on reducing the intake of trans fatty acids (TFAs) because of potential hazards to human health and the increased risk for NASH. However, the health benefits of reducing dietary TFAs have not been fully elucidated. Here, the effects of TFAs vs. a substitute on NASH induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet (CDAA-HF) were investigated. Methods: Mice were fed CDAA-HF containing shortening with TFAs (CDAA-HF-T(+)), CDAA-HF containing shortening without TFAs (CDAA-HF-T(−)), or a control chow for 13 or 26 weeks. Results: At week 13, NASH was induced in mice by feeding CDAA-HF-T(+) containing TFAs or CDAA-HF-T(−) containing no TFAs, but rather mostly saturated fatty acids (FAs), as evidenced by elevated serum transaminase activity and liver changes, including steatosis, inflammation, and fibrosis. CDAA-HF-T(−) induced a greater extent of hepatocellular apoptosis at week 13. At week 26, proliferative (preneoplastic and non-neoplastic) nodular lesions were more pronounced in mice fed CDAA-HF-T(−) than CDAA-HF-T(+). Conclusions: Replacement of dietary TFAs with a substitute promoted the development of proliferation lesions in the liver of a mouse NASH model, at least under the present conditions. Attention should be paid regarding use of TFA substitutes in foods for human consumption, and a balance of FAs is likely more important than the particular types of FAs. [ABSTRACT FROM AUTHOR]

Published
2020
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6. TWEAK/Fn14 Signalling Regulates the Tissue Microenvironment in Chronic Pancreatitis

Author

N. Dianah B. Abu Bakar, Rodrigo Carlessi, Jully Gogoi-Tiwari, Julia Köhn-Gaone, Vincent Williams, Marco Falasca, John K. Olynyk, Grant A. Ramm, and Janina E. E. Tirnitz-Parker

Subjects
Cancer Research, Oncology, choline-deficient, ethionine-supplemented diet, TWEAK/Fn14 signalling, chronic pancreatitis, ductular proliferation, inflammation, fibrosis
Abstract

Chronic pancreatitis increases the risk of developing pancreatic cancer through the upregulation of pathways favouring proliferation, fibrosis, and sustained inflammation. We established in previous studies that the ligand tumour necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) signals through its cognate receptor fibroblast growth factor-inducible 14 (Fn14) to regulate these underlying cellular processes in the chronic liver injury niche. However, the role of the TWEAK/Fn14 signalling pathway in pancreatic disease is entirely unknown. An analysis of publicly available datasets demonstrated that the TWEAK receptor Fn14 is upregulated in pancreatitis and pancreatic adenocarcinoma, with single cell RNA sequencing revealing pancreatic ductal cells as the main Fn14 producers. We then used choline-deficient, ethionine-supplemented (CDE) diet feeding of wildtype C57BL/6J and Fn14 knockout littermates to (a) confirm CDE treatment as a suitable model of chronic pancreatitis and (b) to investigate the role of the TWEAK/Fn14 signalling pathway in pancreatic ductal proliferation, as well as fibrotic and inflammatory cell dynamics. Our time course data obtained at three days, three months, and six months of CDE treatment reveal that a lack of TWEAK/Fn14 signalling significantly inhibits the establishment and progression of the tissue microenvironment in CDE-induced chronic pancreatitis, thus proposing the TWEAK/Fn14 pathway as a novel therapeutic target.

Published
2023
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7. Discovery and development of palmatine analogues as anti-NASH agents by activating farnesoid X receptor (FXR).

Author

Zhang, Na, Fan, Tianyun, Zhao, Liping, Li, Yiming, Bao, Yunyang, Ma, Xican, Mei, Yuheng, Wang, Yanxiang, Liu, Yonghua, Deng, Hongbin, Li, Yinghong, He, Hongwei, and Song, Danqing

Subjects
*HEPATIC fibrosis, *FARNESOID X receptor, *HIGH-fat diet
Abstract

Sixty-one palmatine (PMT) derivatives, of which twenty-eight were new, were synthesized and evaluated for their anti-fibrogenic activities via collagen type I α 1 (COL1A1) -promoter based luciferase model in LX-2 cells, taking 2,3,10-trimethoxy-9- p -isopropyloxyprotopalmatine bromide (1) as the lead. Among them, compound 3a exerted the highest potency with the IC 50 value of 8.19 μmol/L and SI value of 8.59, and reduced the expressions of multiple fibrogenic biomarkers, including COL1A1, TGF-β1, α-SMA and TIMP1 in a dose-dependent manner. In addition, it significantly reduced liver steatosis and inflammation, and especially attenuated the degree of liver fibrosis in choline-deficient, l -amino acid-defined, high-fat diet (CDAHFD)-induced NASH mice model in vivo. Mechanism study indicated that it significantly ameliorated liver injury by activating farnesoid X receptor (FXR). BDL-induced fibrosis rats model further verified its liver-protective and anti-fibrosis activities. Therefore, PMT derivatives constituted a new family of non-steroidal FXR agonists as anti-NASH candidates, with the advantage of good safety profile, and are worthy for further investigation. [Display omitted] • 61 palmatine analogues are prepared and evaluated for their antifibrogenic effects. • 3a inhibits COL1A1 with IC 50 value of 8.19 μmol/L and SI value of 8.59. • 3a exerts reasonable druglike property with high safety and metabolic stability. • 3a ameliorates CDAHFD and BDL-induced liver injury in vivo by activating FXR. [ABSTRACT FROM AUTHOR]

Published
2023
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8. RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease

Author

Medicina, Medikuntza, Afonso, Marta Bento, Rodrigues, Pedro M., Mateus Pinheiro, Miguel, Simao, André L., Gaspar, María M., Majdi, Amine, Arretxe Oliden, Enara, Alonso, Cristina, Santos Laso, Álvaro, Jiménez Agüero, Raúl, Eizaguirre Letamendia, Emma, Bujanda Fernández de Pierola, Luis, Pareja Megía, María J., Bañales Asurmendi, Jesús María, ratziu, Vlad, Gautheron, Jeremie, Castro, Rui E., Rodrigues, Cecilia M. P., Medicina, Medikuntza, Afonso, Marta Bento, Rodrigues, Pedro M., Mateus Pinheiro, Miguel, Simao, André L., Gaspar, María M., Majdi, Amine, Arretxe Oliden, Enara, Alonso, Cristina, Santos Laso, Álvaro, Jiménez Agüero, Raúl, Eizaguirre Letamendia, Emma, Bujanda Fernández de Pierola, Luis, Pareja Megía, María J., Bañales Asurmendi, Jesús María, ratziu, Vlad, Gautheron, Jeremie, Castro, Rui E., and Rodrigues, Cecilia M. P.

Abstract

[EN]Objective Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD. Design RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3(-/-)) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks. Results RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3(-/-) mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3(-/-) mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor. (PPAR.) was increased in Ripk3(-/-) mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPAR. in controlling fat deposition and fibrosis. Conclusion Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.

Published
2021

9. Hypoxia-inducible factor–1α–dependent induction of miR122 enhances hepatic ischemia tolerance

Author

J. Steve Bynon, Yafen Liang, Boyun Kim, Yang Yang, Wasim A. Dar, Cynthia Ju, Meng Wang, David R. Hall, Holger K. Eltzschig, Peter Carmeliet, Christoph Emontzpohl, Huban Kutay, Xiaoyi Yuan, Eunyoung Tak, and Kalpana Ghoshal

Subjects
0301 basic medicine, Male, medicine.medical_treatment, Genetic enhancement, Mice, Transgenic, Research & Experimental Medicine, Liver transplantation, MIR-122, CHOLINE-DEFICIENT, 03 medical and health sciences, Mice, 0302 clinical medicine, CIRCULATING MICRORNAS, Ischemia, microRNA, REPERFUSION, Medicine, Animals, Humans, PROTECTS LIVERS, Psychological repression, IN-VIVO, Liver injury, Science & Technology, business.industry, Liver Diseases, General Medicine, SERUM-LEVELS, Hypoxia (medical), medicine.disease, Hypoxia-Inducible Factor 1, alpha Subunit, Transplantation, MicroRNAs, 030104 developmental biology, Medicine, Research & Experimental, Hypoxia-inducible factors, Liver, 030220 oncology & carcinogenesis, Reperfusion Injury, Cancer research, Hepatocytes, Female, LIVER-INJURY, medicine.symptom, OXYGEN SENSORS, business, Life Sciences & Biomedicine, KISSING COMPLEX, Research Article
Abstract

Hepatic ischemia and reperfusion (IR) injury contributes to the morbidity and mortality associated with liver transplantation. microRNAs (miRNAs) constitute a family of noncoding RNAs that regulate gene expression at the posttranslational level through the repression of specific target genes. Here, we hypothesized that miRNAs could be targeted to enhance hepatic ischemia tolerance. A miRNA screen in a murine model of hepatic IR injury pointed us toward the liver-specific miRNA miR122. Subsequent studies in mice with hepatocyte-specific deletion of miR122 (miR122loxP/loxP Alb-Cre+ mice) during hepatic ischemia and reperfusion revealed exacerbated liver injury. Transcriptional studies implicated hypoxia-inducible factor-1α (HIF1α) in the induction of miR122 and identified the oxygen-sensing prolyl hydroxylase domain 1 (PHD1) as a miR122 target. Further studies indicated that HIF1α-dependent induction of miR122 participated in a feed-forward pathway for liver protection via the enhancement of hepatic HIF responses through PHD1 repression. Moreover, pharmacologic studies utilizing nanoparticle-mediated miR122 overexpression demonstrated attenuated liver injury. Finally, proof-of-principle studies in patients undergoing orthotopic liver transplantation showed elevated miR122 levels in conjunction with the repression of PHD1 in post-ischemic liver biopsies. Taken together, the present findings provide molecular insight into the functional role of miR122 in enhancing hepatic ischemia tolerance and suggest the potential utility of pharmacologic interventions targeting miR122 to dampen hepatic injury during liver transplantation. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:131 issue:7 ispartof: location:United States status: published

Published
2021

10. RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease

Author

Raul Jimenez-Agüero, María Jesús Pareja, Alvaro Santos-Laso, Jérémie Gautheron, Emma Eizaguirre, Jesus M. Banales, André L. Simão, Marta B. Afonso, Enara Arretxe, Cristina Alonso, Vlad Ratziu, Rui E. Castro, Miguel Mateus-Pinheiro, Cecília M. P. Rodrigues, Pedro Rodrigues, Luis Bujanda, Maria Manuela Gaspar, Amine Majdi, Faculdade de Farmácia da Universidade de Lisboa, Universidade de Lisboa = University of Lisbon (ULISBOA), Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universidad del Pais Vasco / Euskal Herriko Unibertsitatea [Espagne] (UPV/EHU), Service d'Hépato-Gastro-Entérologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Gestionnaire, Hal Sorbonne Université, Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP)

Subjects
Liver Cirrhosis, choline-deficient, Carcinogenesis, hepatocellular-carcinoma, molecular carcinogenesis, Chronic liver disease, Pathogenesis, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, Fibrosis, lipid metabolism, Prospective Studies, nonalcoholic steatohepatitis, 0303 health sciences, Liver Neoplasms, Fatty liver, hepatocarcinogenesis, Gastroenterology, activated receptor-gamma, 3. Good health, Cell Transformation, Neoplastic, cell death, Receptor-Interacting Protein Serine-Threonine Kinases, Disease Progression, 030211 gastroenterology & hepatology, protects, medicine.symptom, medicine.medical_specialty, mice, Necroptosis, necroptosis, Inflammation, [SDV.CAN]Life Sciences [q-bio]/Cancer, 03 medical and health sciences, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, 030304 developmental biology, Hepatology, business.industry, fibrosis, chronic liver disease, Lipid metabolism, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, cell, medicine.disease, gene-expression, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Endocrinology, Steatohepatitis, business, Biomarkers
Abstract

[EN]Objective Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD. Design RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3(-/-)) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks. Results RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3(-/-) mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3(-/-) mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor. (PPAR.) was increased in Ripk3(-/-) mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPAR. in controlling fat deposition and fibrosis. Conclusion Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression. Main funding is provided by FEDER funds through the COMPETE programme and by national funds through Fundacao para a Ciencia e a Tecnologia to CMPR (grants SAICTPAC/0019/2015-LISBOA-01-0145--FEDER-016405 and PTDC/MED-FAR/29097/2017 -LISBOA-01-0145-FEDER-029097). Additional funding comes from research grant APEF (Portuguese Association for the Study of Liver)/BAYER 2020 to MBA. JG is funded by the Fondation pour la Recherche Medicale (ARF20170938613), the Institute of Cardiometabolism and Nutrition (PAP17NECJG), the Societe Francophone du Diabete (R19114DD) and the Mairie de Paris (Emergences -R18139DD). MBA, PMR, MMP and ALS were investigators or students funded by Fundacao para a Ciencia e a Tecnologia.

Published
2021
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11. A trans fatty acid substitute enhanced development of liver proliferative lesions induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet

Author

Megumi Yuki, Shuji Ogawa, Akari Abe, Dai Nakae, Ryuhei Sano, Noriko Suzuki-Kemuriyama, Kiniko Uno, Katsuhiro Miyajima, and Atsushi Watanabe

Subjects
Male, 0301 basic medicine, Cirrhosis, Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Apoptosis, Choline, Methionine-lowered, Mice, Liver disease, chemistry.chemical_compound, Methionine, 0302 clinical medicine, Endocrinology, Non-alcoholic Fatty Liver Disease, Amino Acids, Insulin-Like Growth Factor I, Phosphorylation, lcsh:RC620-627, chemistry.chemical_classification, Chemistry, Choline-deficient, L-amino acid-defined, NF-kappa B, Organ Size, Trans Fatty Acids, Choline Deficiency, lcsh:Nutritional diseases. Deficiency diseases, High-fat diet, Liver, 030211 gastroenterology & hepatology, Sulfotransferases, medicine.medical_specialty, Clinical chemistry, Diet, High-Fat, Transaminase, 03 medical and health sciences, Internal medicine, medicine, Trans fatty acid substitutes, Animals, Humans, Nonalcoholic steatohepatitis, Inflammation, Gene Expression Profiling, Research, Body Weight, Biochemistry (medical), Correction, Fatty acid, medicine.disease, Animal Feed, Soybean Oil, Fatty Liver, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, RNA, Steatosis
Abstract

Background Nonalcoholic steatohepatitis (NASH) is a form of liver disease characterized by steatosis, necroinflammation, and fibrosis, resulting in cirrhosis and cancer. Efforts have focused on reducing the intake of trans fatty acids (TFAs) because of potential hazards to human health and the increased risk for NASH. However, the health benefits of reducing dietary TFAs have not been fully elucidated. Here, the effects of TFAs vs. a substitute on NASH induced in mice by feeding a choline-deficient, methionine-lowered, L-amino acid-defined, high-fat diet (CDAA-HF) were investigated. Methods Mice were fed CDAA-HF containing shortening with TFAs (CDAA-HF-T(+)), CDAA-HF containing shortening without TFAs (CDAA-HF-T(−)), or a control chow for 13 or 26 weeks. Results At week 13, NASH was induced in mice by feeding CDAA-HF-T(+) containing TFAs or CDAA-HF-T(−) containing no TFAs, but rather mostly saturated fatty acids (FAs), as evidenced by elevated serum transaminase activity and liver changes, including steatosis, inflammation, and fibrosis. CDAA-HF-T(−) induced a greater extent of hepatocellular apoptosis at week 13. At week 26, proliferative (preneoplastic and non-neoplastic) nodular lesions were more pronounced in mice fed CDAA-HF-T(−) than CDAA-HF-T(+). Conclusions Replacement of dietary TFAs with a substitute promoted the development of proliferation lesions in the liver of a mouse NASH model, at least under the present conditions. Attention should be paid regarding use of TFA substitutes in foods for human consumption, and a balance of FAs is likely more important than the particular types of FAs.

Published
2020

12. Molecular pathology of acute kidney injury in a choline-deficient model and fish oil protective effect.

Author

Denninghoff, Valeria, Ossani, Georgina, Uceda, Ana, Rugnone, Matias, Fernández, Elmer, Fresno, Cristóbal, González, German, Díaz, Maria, Avagnina, Alejandra, Elsner, Boris, and Monserrat, Alberto

Subjects
*ACUTE kidney failure prevention, *GENES, *RNA analysis, *ANALYSIS of variance, *ANIMAL experimentation, *BIOLOGICAL assay, *BIOPHYSICS, *CHOLINE, *COMPARATIVE studies, *DIETARY supplements, *FISH oils, *FOLIC acid, *GRAPHIC arts, *HISTOLOGICAL techniques, *KIDNEYS, *RESEARCH methodology, *RATS, *RESEARCH funding, *STAINS & staining (Microscopy), *STATISTICS, *U-statistics, *HOMOCYSTEINE, *DATA analysis, *DESCRIPTIVE statistics
Abstract

Purpose: The aim of this work was to investigate the potential protective effects of fish oil on the basis of kidney transcriptomic data on a nutritional experimental model. Methods: Male weanling Wistar rats were divided into four groups and fed choline-deficient (CD) and choline-supplemented (CS) diets with vegetable oil (VO) and menhaden oil (MO): CSVO, CDVO, CSMO and CDMO. Animals were killed after receiving the diets for 6 days. Total RNA was purified from the right kidney and hybridized to Affymetrix GeneChip Rat Gene 1.0 ST Array. Differentially expressed genes were analyzed. Results: All CSVO, CSMO and CDMO rats showed no renal alterations, while all CDVO rats showed renal cortical necrosis. A thorough analysis of the differential expression between groups CSMO and CDMO was carried out. There were no differential genes for p < 0.01. The analysis of the differential expression between groups CSVO and CSMO revealed 32 genes, 11 were over-expressed and 21 were under-expressed in CSMO rats. Conclusions: This work was part of a large set of experiments and was used in a hypothesis-generating manner. The comprehensive analysis of genetic expression allowed confirming that menhaden oil has a protective effect on this nutritional experimental model and identifying 32 genes that could be responsible for that protection, including Gstp1. These results reveal that gene changes could play a role in renal injury. [ABSTRACT FROM AUTHOR]

Published
2014
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13. Bone marrow cells play only a very minor role in chronic liver regeneration induced by a choline-deficient, ethionine-supplemented diet.

Author

Tonkin, Joanne N., Knight, Belinda, Curtis, David, Abraham, Lawrence J., and Yeoh, George C.T.

Subjects
BONE marrow cells, HEMATOPOIETIC system, LIVER diseases, STEM cell research
Abstract

Abstract: Liver progenitor (oval) cells have enormous potential in the treatment of patients with liver disease using a cell therapy approach, but their use is limited by their scarcity and the number of donor livers from which they can be derived. Bone marrow may be a suitable source. Previously the derivation of oval cells from bone marrow was examined in rodents using hepatotoxins and partial hepatectomy to create liver damage. These protocols induce oval cell proliferation; however, they do not produce the disease conditions that occur in humans. In this study we have used the choline-deficient, ethionine-supplemented (CDE) diet (which causes fatty liver) and viral hepatitis as models of chronic injury to evaluate the contribution of bone marrow cells to oval cells under conditions that closely mimic human liver disease pathophysiology. Following transplantation of lacZ-transgenic bone marrow cells into congenic mice, liver injury was induced and the movement of bone marrow cells to the liver monitored. Bone marrow-derived oval cells were observed in response to the CDE diet and viral injury but represented a minor fraction (0–1.6%) of the oval cell compartment, regardless of injury severity. In all situations only rare, individual bone marrow-derived oval cells were observed. We hypothesized that the bone marrow cells may replenish oval cells that are expended by protracted liver injury and regeneration; however, experiments involving a subsequent episode of chronic liver injury failed to induce proliferation of the bone marrow-derived oval cells that appeared as a result of the first episode. Bone marrow-derived hepatocytes were also observed in all injury models and controls at a frequency unrelated to that of oval cells. We conclude that during viral-and steatosis-induced liver disease the contribution of bone marrow cells to hepatocytes, either via oval cells or by independent mechanisms, is minimal and that the majority of oval cells responding to this injury are sourced from the liver. [Copyright &y& Elsevier]

Published
2008
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14. C-kit Inhibition by Imatinib Mesylate Attenuates Progenitor Cell Expansion and Inhibits Liver Tumor Formation in Mice.

Author

Knight, Belinda, Tirnitz–Parker, Janina E.E., and Olynyk, John K.

Subjects
AMINO acids, LIVER diseases, DISEASES, DRUG therapy
Abstract

Background & Aims: Numerous studies have linked the proliferation of liver progenitor cells (LPCs) during chronic liver disease to the risk for development of hepatocellular carcinoma. Thus, selective inhibition of LPC growth during preneoplastic injury may prevent or delay the onset of liver cancer. Rats carrying a germ-line mutation in c-kit have an impaired LPC response to liver injury. Therefore, we hypothesized that the c-kit inhibitor imatinib mesylate (IM) would suppress LPC growth and, therefore, may exert antitumorigenic effects in the liver. Methods: Expression of IM target proteins was examined in chronically injured rodent and human livers. The effect of IM was examined in vitro using LPC lines and in vivo in mice fed a choline-deficient, ethionine-supplemented (CDE) diet. Livers were examined following short-term (up to 1 month) or long-term (up to 14 months) feeding of CDE diet and drug treatments. Results: C-kit was significantly up-regulated in chronic injury and expressed by LPCs. IM was antiproliferative to LPC lines, and knockdown of c-kit reduced this response. IM treatment inhibited the LPCs response and early fibrogenesis induced by a short-term CDE diet. On the longer term, IM treatment reduced the extent of fibrosis and significantly inhibited tumor formation. Conclusions: Tyrosine kinase inhibitors, such as IM, may be suited for the prevention of hepatocellular carcinoma in the setting of chronic liver injury via antiproliferative effects on c-kit-expressing LPCs. [Copyright &y& Elsevier]

Published
2008
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15. Choline cannot be replaced by propanolamine in mice

Author

Li, Zhaoyu and Vance, Dennis E.

Subjects
*VITAMIN B complex, *CHOLINE, *LECITHIN, *BILIARY tract
Abstract

Abstract: Choline is an important nutrient for humans and animals. Animals obtain choline from the diet and from the catabolism of phosphatidylcholine made by phosphatidylethanolamine N-methyltransferase (PEMT). The unique model of complete choline deprivation is Pemt −/− mice that are fed a choline-deficient diet. This model, therefore, can be used for the examination of choline substitutes in mammalian systems. Recently, propanolamine was found to be a replacement for choline in yeast. Thus, we tested to see whether or not choline can be replaced by propanolamine in mice. Mice were fed a choline-deficient diet and supplemented with either methionine, 2-amino-propanol, 2-amino-isopropanol and 3-amino-propanol. We were unable to detect the formation of any of the possible phosphatidylpropanolamines. Moreover, none of them prevented liver damage, reduction of hepatic phosphatidylcholine levels or fatty liver induced in choline-deficient-Pemt −/− mice. These results suggest that choline in mice cannot be replaced by any of the three propanolamine derivatives. [Copyright &y& Elsevier]

Published
2007
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16. Dimethylethanolamine does not prevent liver failure in phosphatidylethanolamine N-methyltransferase-deficient mice fed a choline-deficient diet

Author

Waite, Kristin A. and Vance, Dennis E.

Subjects
*DIMETHYLAMINOETHANOL, *LIVER failure, *METHYLTRANSFERASES, *CHOLINE
Abstract

Mice that lack phosphatidylethanolamine-N-methyltransferase (PEMT) and are fed a choline-deficient (CD) diet suffer severe liver damage and do not survive. Since phosphatidyldimethylethanolamine (PDME) has physical properties similar to those of phosphatidylcholine (PC), we hypothesized that dimethylethanolamine (DME) would be converted into PDME that might substitute for PC, and therefore abrogate the liver damage in the Pemt-/- mice fed a CD diet. We fed Pemt-/- mice either a CD diet, a CD diet supplemented with choline, or a CD diet supplemented with DME (CD+DME). Pemt-/- mice fed the CD diet developed severe liver failure by 4 days while CD+DME-fed mice developed severe liver failure by 5 days. The hepatic PC level in choline-supplemented (CS) mice was 67±4 nmol/mg protein, whereas the PC content was reduced in CD- and CD+DME-fed mice (49±3 and 30±3 nmol/mg protein, respectively). Upon supplementation of the CD diet with DME the amount of hepatic PDME was 81±9 nmol/mg protein so that the hepatic content of PC+PDME combined was 111 nmol/mg protein. Moreover, plasma apolipoprotein B100 and A1 levels were markedly lower in mice fed the CD+DME diet compared to mice fed the CS diet, as was the plasma content of PC. Thus, despite replacement of the deficit in hepatic PC with PDME in Pemt-/- mice fed a CD diet, normal liver function was not restored. We conclude that although PC and PDME exhibit similar physical properties, the three methyl groups of choline are required for hepatic function in mice. [Copyright &y& Elsevier]

Published
2004
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17. Influência da disbiose intestinal no risco cardiovascular em modelo experimental híbrido de doença hepática gordurosa não-alcoólica em ratos

Author

Longo, Larisse, Álvares-da-Silva, Mário Reis, and Cruz, Carolina Uribe

Subjects
Doenças cardiovasculares, High-fat diet, Figado gorduroso, Dieta hiperlipidica, Choline-deficient, Gut microbiota, Cardiovascular risk, Non-alcoholic fatty liver disease
Abstract

Introdução: A doença hepática gordurosa não-alcoólica (DHGNA) é uma doença hepática progressiva que é considerada um fator de risco para o desenvolvimento de doença cardiovascular (DCV). Transtornos do eixo fígado-intestino, incluindo a disbiose intestinal, têm sido associados à DHGNA e DCV. Objetivos: Desenvolver um modelo experimental de DHGNA de origem metabólica que permita avaliar, na sequência, fatores relacionados à DCV, como índices aterogênicos, inflamação hepática e sistêmica e disfunção endotelial, bem como a associação entre a composição e a diversidade da microbiota intestinal e sua relação com o risco de desenvolvimento de DVC. Métodos: Ratos Sprague Dawley, adultos e machos, foram randomizados em dois grupos (n=10): controle, alimentado com dieta padrão, e intervenção, que recebeu dieta hiperlipídica deficiente em colina. O experimento teve duração de 16 semanas e após os animais foram eutanasiados. Os materiais biológicos foram coletados e armazenados até a realização das avaliações bioquímicas, inflamatórias, histológicas e da microbiota fecal. Resultados: Os animais do grupo intervenção apresentaram significativo aumento no delta de índice de Lee (p = 0,017), circunferência abdominal (p < 0,001), acúmulo de tecido adiposo abdominal (p < 0,001), bem como elevação dos níveis séricos de alanina aminotransferase (p = 0,010), glicemia (p = 0,013), colesterol total (p = 0,033), lipoproteína de baixa densidade (p = 0,011) e triglicerídeos (p = 0,011) e diminuição dos níveis séricos de lipoproteína de alta densidade (p = 0,006), similares às observadas na DHGNA em humanos. Todos os animais do grupo intervenção desenvolveram DHGNA, com ou sem a presença de esteato-hepatite, enquanto no grupo controle não houve qualquer alteração histológica. Houve aumento significativo no grupo intervenção dos índices aterogênicos, coeficiente aterogênico (p < 0,001), índice de risco Castelli-I (p < 0,001) e índice de risco Castelli-II (p < 0,001), além de aumento significativo na concentração dos marcadores de inflamação e disfunção endotelial sistêmica, interleucina (IL)-1β (p < 0,001), proteína quimiotática de monócitos-1 (p < 0,001), inibidor tecidual de metaloproteinases-1 (p < 0,001) e inibidor do ativador de plasminogênio-1 (p < 0,019). Houve um aumento na expressão gênica hepática do receptor toll like (TLR)-4 (p = 0,041), TLR-9 (p = 0,033), fator de diferenciação mielóide-88 (p = 0,001), receptor do tipo NOD-proteína-3 (p = 0,019), capase-1 (p < 0,001), fator de necrose tumoral-α (p = 0,028), IL-6 (p = 0,013) e IL-18 (p = 0,007), além da diminuição das expressão do receptor ativado por proliferadores de peroxissoma-α (p = 0,008) em relação ao grupo controle. Observamos aumento significativo de miR-122 (p = 0,041) e miR-33a (p = 0,001) no grupo intervenção, e o inverso foi observado para miR-145 (p = 0,010) e miR-126 (p < 0,001). O grupo intervenção, apresentou diminuição significativa da diversidade bacteriana fecal e menor abundância relativa do filo Firmicutes (p = 0,040), o que se correlacionou com a gravidade histológica da DHGNA. Conclusão: O grupo intervenção apresentou alterações bioquímicas, inflamatórias e histopatológicas similares àquelas observadas na DHGNA em humanos. Houve neste grupo, um aumento da obesidade visceral, dislipidemia, hiperglicemia, inflamação hepática e sistêmica, disfunção endotelial e um maior risco de desenvolvimento de DCV. Este modelo experimental, poderia ser utilizado no entendimento da fisiopatologia da DHGNA e sua evolução, bem como para estudos terapêuticos pré-clínicos que visem à cardioproteção na DHGNA, um desfecho habitualmente não avaliado em ensaios clínicos em humanos. Introduction: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease that is considered a risk factor for the development of cardiovascular disease (CVD). Liver-gut axis disorders, including intestinal dysbiosis, have been associated with NAFLD and CVD. Objective: To develop an experimental model of NAFLD of metabolic origin that would allow to evaluate, in the sequence, factors related to CVD, such as atherogenic indices, hepatic and systemic inflammation and endothelial dysfunction, as well as the association between the composition and diversity of the gut microbiota and its relationship with the risk of developing CVD. Methods: Adult male Sprague Dawley rats were randomized into two groups (n = 10): control group that was fed standard diet and intervention group that received a high-fat and choline-deficient (HFCD) diet. The experiment had duration of 16 weeks and after the animals were euthanized. Biological materials were collected and stored until the biochemical, inflammatory, histological and fecal microbiota evaluations were performed. Results: The animals in the intervention group, showed a significantly greater delta Lee index (p = 0.017), abdominal circumference (p < 0.001), abdominal adipose tissue accumulation (p < 0.001), as well as elevation of serum levels of alanine aminotransferase (p = 0.010), glycemic (p = 0.013), total cholesterol (p = 0.033), low-density lipoprotein (p = 0.011), triglycerides (p = 0.011) and decreased serum levels of high-density lipoprotein (p = 0.006), corresponding to those observed in NAFLD in humans. All animals in the intervention group developed NAFLD, with or without the presence of steatohepatitis, while no histological changes were found in the control group. There was a significant increase in the intervention group, of atherogenic indices, atherogenic coefficient (p < 0.001), Castelli-I risk index (p < 0.001) and Castelli-II risk index (p < 0.001), increased markers of systemic inflammation and endothelial dysfunction, interleukin (IL)-1β (p < 0.001), monocyte chemotactic protein-1 (p < 0.001), tissue inhibitor of metalloproteinases-1 (p < 0.001) and inhibitor of plasminogen activator-1 (p < 0.019). There was an increase in hepatic gene expression of toll-like receptor (TLR)-4 (p = 0.041), TLR-9 (p = 0.033), myeloid differentiation primary response-88 (p = 0.001), nod-like receptor protein-3 (p = 0.019) caspase-1 (p < 0.001), tumor necrosis factor-α (p = 0.028), IL-6 (p = 0.013) and IL-18 (p = 0.007), besides the diminution of the expression of peroxisome proliferator activated receptor-α (p = 0.008) in relation to the control group. We observed a significant increase of miR-122 (p = 0.041) and miR-33a (p = 0.001) in the intervention group, and the inverse was observed for miR-145 (p = 0.010) and miR-126 (p < 0.001). The intervention group showed a significant decrease in the fecal bacterial diversity and lower relative abundance of the Firmicutes phylum (p = 0.040), which correlated with the histological severity of NAFLD. Conclusion: The intervention group presented biochemical, inflammatory and histopathological alterations, similar to those observed in NAFLD in humans. There were in this group, an increase in visceral obesity, dyslipidemia, hyperglycemia, systemic and hepatic inflammation, endothelial dysfunction and an increased risk of developing CVD. This experimental model could be used to understand the pathophysiology of NAFLD and its evolution, as well as for preclinical therapeutic studies that aim at cardioprotection in NAFLD, an outcome not usually evaluated in clinical trials in humans.

Published
2018

18. Molecular pathology of acute kidney injury in a choline-deficient model and fish oil protective effect

Author

Cristóbal Fresno, Valeria Denninghoff, Boris Elsner, Ana Uceda, German González, Georgina P. Ossani, Matias Rugnone, Maria L. Diaz, Alejandra Avagnina, Alberto J. Monserrat, and Elmer Andrés Fernández

Subjects
Male, GENE EXPRESSION, Pathology, medicine.medical_specialty, ACUTE KIDNEY INJURY, Medicine (miscellaneous), Weaning, MENHADEN OIL, PROTECTIVE EFFECT, Biology, Kidney, Choline, CHOLINE-DEFICIENT, Ciencias Biológicas, chemistry.chemical_compound, Necrosis, Fish Oils, medicine, Animals, Métodos de Investigación en Bioquímica, Rats, Wistar, Oligonucleotide Array Sequence Analysis, RNA metabolism, Nutrition and Dietetics, Molecular pathology, Gene Expression Profiling, Acute kidney injury, Kidney pathology, Kidney metabolism, Acute Kidney Injury, medicine.disease, Fish oil, Molecular biology, Choline Deficiency, Up-Regulation, chemistry, Glutathione S-Transferase pi, Dietary Supplements, RNA, Transcriptome, CIENCIAS NATURALES Y EXACTAS, Biomarkers
Abstract

The aim of this work was to investigate the potential protective effects of fish oil on the basis of kidney transcriptomic data on a nutritional experimental model. Methods Male weanling Wistar rats were divided into four groups and fed choline-deficient (CD) and choline-supplemented (CS) diets with vegetable oil (VO) and menhaden oil (MO): CSVO, CDVO, CSMO and CDMO. Animals were killed after receiving the diets for 6 days. Total RNA was purified from the right kidney and hybridized to Affymetrix GeneChip Rat Gene 1.0 ST Array. Differentially expressed genes were analyzed. Results All CSVO, CSMO and CDMO rats showed no renal alterations, while all CDVO rats showed renal cortical necrosis. A thorough analysis of the differential expression between groups CSMO and CDMO was carried out. There were no differential genes for p < 0.01. The analysis of the differential expression between groups CSVO and CSMO revealed 32 genes, 11 were over-expressed and 21 were under-expressed in CSMO rats. Conclusions This work was part of a large set of experiments and was used in a hypothesis-generating manner. The comprehensive analysis of genetic expression allowed confirming that menhaden oil has a protective effect on this nutritional experimental model and identifying 32 genes that could be responsible for that protection, including Gstp1. These results reveal that gene changes could play a role in renal injury. Fil: Denninghoff, Valeria Cecilia. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ossani, Georgina Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentina Fil: Uceda, Ana Margarita. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentina Fil: Rugnone, Matias Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Fernandez, Elmer Andres. Area de Ciencias Agrarias, Ingeniería, Ciencias Biológicas y de la Salud de la Universidad Católica de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina Fil: Fresno Rodríguez, Cristóbal. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba; Argentina. Area de Ciencias Agrarias, Ingeniería, Ciencias Biológicas y de la Salud de la Universidad Católica de Córdoba; Argentina Fil: González, German. Area de Ciencias Agrarias, Ingeniería, Ciencias Biológicas y de la Salud de la Universidad Católica de Córdoba; Argentina Fil: Díaz, Maria Luisa. Hospital Británico de Buenos Aires; Argentina Fil: Avagnina, Alejandra. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina Fil: Elsner, Boris. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina Fil: Monserrat, Alberto Juan. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Patología. Centro de Patología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

Published
2012

19. The murine choline-deficient, ethionine-supplemented (CDE) diet model of chronic liver injury

Author

Gogoi-Tiwari, Jully, Köhn-Gaone, Julia, Giles, Corey, Schmidt-Arras, Dirk E., Gratte, Francis D., Elsegood, Caryn L., McCaughan, Geoffrey W., Ramm, Grant A., Olynyk, John K., Tirnitz-Parker, Janina E., Gogoi-Tiwari, Jully, Köhn-Gaone, Julia, Giles, Corey, Schmidt-Arras, Dirk E., Gratte, Francis D., Elsegood, Caryn L., McCaughan, Geoffrey W., Ramm, Grant A., Olynyk, John K., and Tirnitz-Parker, Janina E.

Abstract

Gogoi-Tiwari, J., Köhn-Gaone, J., Giles, C., Schmidt-Arras, D., Gratte, F. D., Elsegood, C. L., ... & Tirnitz-Parker, J. E. (2017). The Murine Choline-Deficient, Ethionine-Supplemented (CDE) Diet Model of Chronic Liver Injury. Journal of visualized experiments: JoVE, (128). Available here.

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