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Zhao Y, Li JZ, Liu YG, Zhu YJ, Zhang Y, Zheng WW, Ma L, Li J, Wang CY. Clinical features and prognosis of drug-induced liver injury in patients with non-alcoholic fatty liver. World J Hepatol 2025; 17:101741. [PMID: 40027577 PMCID: PMC11866136 DOI: 10.4254/wjh.v17.i2.101741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 11/28/2024] [Accepted: 12/25/2024] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Acute drug-induced liver injury (DILI) events caused by chronic liver disease are relatively common. Some researchers believe that nonalcoholic fatty liver (NAFL) increases the overall risk of DILI. The clinical characteristics and prognosis of DILI in the context of NAFL disease (NAFLD) are still unclear. Therefore, hospitalized patients with NAFLD combined with DILI at the Tianjin Second People's Hospital were included in this study. The clinical manifestations, classifications, severities, laboratory indicators, and clinical outcomes of the enrolled patients were analyzed, and the clinical characteristics and prognoses of the NAFL + DILI patients were evaluated. AIM To investigate the clinical characteristics and prognosis of DILI in the context of NAFL. METHODS Eighty-nine patients diagnosed with DILI and 110 patients diagnosed with both DILI and NAFL at the Tianjin Second People's Hospital were enrolled. Clinical data, including demographic characteristics, clinical features, laboratory test results, pathology findings, autoantibody titers, suspected drugs, and outcomes, were collected from the two groups of patients. All enrolled patients were followed up to determine the liver function recovery time. RESULTS Compared with the patients in the DILI group, those in the NAFL + DILI group had higher body mass indices; Controlled Attenuation Parameter scores; and triglyceride, total cholesterol, low-density lipoprotein, and insulin levels. The levels of the cytokines interleukin-4 and complement complement c3 (C3) were also greater in the NAFL + DILI group than in the DILI group. The proportions of patients with cholestatic-type DILI (16.4% vs 4.5%), cholestasis seen on pathoscopy (40.9% vs 25.8%), grade 2 or above DILI (48.18% vs 40.45%), and a recovery time for liver function ranging from 90 to 180 days (30.6% vs 15.5%) were greater in the NAFL + DILI group than in the DILI group. All of the abovementioned differences between the groups were statistically significant (P < 0.05). The autoantibody positivity rates did not significantly differ between the two groups (P > 0.05), and the proportions of patients who progressed to chronic drug hepatitis or autoimmune hepatitis were not significantly different between the two groups (both P > 0.05). CONCLUSION In the context of NAFL, DILI is more likely to be cholestatic, with a greater degree of liver injury, a longer recovery time, and more pronounced expression of immune factors.
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Affiliation(s)
- Ying Zhao
- Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Jian-Zhou Li
- Diagnosis and Treatment Center of High Altitude Digestive Disease, Xining Second People's Hospital, Xining 810003, Qinghai Province, China
| | - Yong-Gang Liu
- Department of Pathology, Tianjin Second People's Hospital, Tianjin 300110, China
| | - Yu-Jin Zhu
- Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Yan Zhang
- Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Wen-Wen Zheng
- Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Lin Ma
- Graduate School, Tianjin Medical University, Tianjin 300070, China
| | - Jia Li
- Department of Gastroenterology, Tianjin Second People's Hospital, Tianjin 300110, China
| | - Chun-Yan Wang
- Department of Gastroenterology, Tianjin Second People's Hospital, Tianjin 300110, China.
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Backer S, Khanna D. The Lasting Effects of COVID-19 on the Progression of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Cureus 2023; 15:e45231. [PMID: 37842470 PMCID: PMC10576539 DOI: 10.7759/cureus.45231] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 09/13/2023] [Indexed: 10/17/2023] Open
Abstract
It is estimated that around 30% of the population living in Western countries has metabolic dysfunction-associated steatotic liver disease (MASLD), a spectrum of pathology (not attributed to alcohol/substance intake) initiated by steatosis and progression toward inflammation and irreversible fibrosis metabolic dysfunction-associated steatohepatitis (MASH). With inflammation being a key component of the transition to MASH, it raises the question of whether the ongoing COVID-19 pandemic, which has notoriously induced hyperinflammatory states, may influence the progression of MASLD. Specifically, it remains unclear if the potential chronic sequelae of COVID-19 in patients who recovered from it may increase the predisposition for MASH. Since MASH maintains a high risk for hepatocellular carcinoma, liver failure, and the need for a liver transplant, the potential additive effects of COVID-19 could prove critical to study. Thus, the objective of this study was to conduct a literature review to examine if COVID-19 could have chronic sequelae that affect the progression of MASLD pathogenesis. It was hypothesized that severe cases of COVID-19 could induce systemic inflammation, metabolic changes, and lasting gut microbiome alterations that lead to inflammatory and fibrotic changes in the liver, similar to those seen in MASH. A scoping review of the literature was conducted utilizing the PubMed database. Studies that examined hepatobiliary pathology, gut microbiome, systemic inflammation, metabolic changes, drug-induced liver injury (DILI), and hypoxia seen in COVID-19 were included. Human studies of adult cohorts, animal models, and in vitro experiments were included. Genetic components of MASLD were not examined. Exclusion criteria also encompassed any studies not referencing the hepatobiliary, gastrointestinal tract, portal system, or systemic circulation. Findings indicated a frequent trend of elevated liver enzymes, mild steatosis, Kupffer cell hyperplasia, and hepatobiliary congestion. It was found that direct cytopathic effects on hepatocytes were unlikely, but the direct viral insult of cholangiocytes was a potential complication. High serum levels of IL-1, TNF-a, and MCP-1, in COVID-19 were found as potential risk factors for MASH development. Hypoxia, altered lipid metabolism, and iatrogenic DILI were also proposed as potential precipitators of MASH development. Notably, lasting changes in gut microbiome were also frequently observed and correlated closely with those seen in MASH.
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Affiliation(s)
- Sean Backer
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA
| | - Deepesh Khanna
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Clearwater, USA
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Wu JX, He Q, Zhou Y, Xu JY, Zhang Z, Chen CL, Wu YH, Chen Y, Qin LQ, Li YH. Protective effect and mechanism of lactoferrin combined with hypoxia against high-fat diet induced obesity and non-alcoholic fatty liver disease in mice. Int J Biol Macromol 2023; 227:839-850. [PMID: 36563804 DOI: 10.1016/j.ijbiomac.2022.12.211] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
Obesity is a global epidemic, it can induce glucose and lipid metabolism disorder and non-alcoholic fatty liver disease (NAFLD). This study explored a new way to control weight and improve fatty liver, namely, living in hypoxia environment and supplement with lactoferrin (Lf). Sixty male C57BL/6J mice were divided into six groups, namely, control, hypoxia, high-fat diet, hypoxia + high-fat diet, hypoxia + high-fat diet + low dose Lf intervention, and hypoxia + high-fat diet + high-dose Lf intervention. Mice in the hypoxia treatment groups were treated with approximately 11.5 % oxygen for 6 h every day for 8 weeks. Results showed that interventions combining Lf and hypoxia treatments showed better effect against obesity and NAFLD than hypoxia treatment alone. The interventions controlled weight gain in mice, improved glucolipid metabolism in mice. The combination intervention reduced cholesterol absorption by reducing the level of hydrophobic bile acids, and elevating the level of hydrophilic bile acids. Gut microbiota analysis revealed that the combination intervention considerably elevated short chain fatty acids (SCFAs)-producing bacteria level, and reduced the Desulfovibrionaceae_unclassified level. Thus, Lf combined with hypoxia intervention effectively prevents obesity and NAFLD by restoring gut microbiota composition and bile acid profile.
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Affiliation(s)
- Jiang-Xue Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical college of Soochow University, Suzhou, Jiangsu, China
| | - Qian He
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical college of Soochow University, Suzhou, Jiangsu, China
| | - Yan Zhou
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical college of Soochow University, Suzhou, Jiangsu, China
| | - Jia-Ying Xu
- State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Suzhou Medical college of Soochow University, Suzhou, Jiangsu, China
| | - Zheng Zhang
- Center of Child Health Management, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Cai-Long Chen
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical college of Soochow University, Suzhou, Jiangsu, China; Center of Child Health Management, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Yun-Hsuan Wu
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical college of Soochow University, Suzhou, Jiangsu, China
| | - Yun Chen
- Food Science School, Guangdong Pharmaceutical University, Zhongshan, Guangdong, China
| | - Li-Qiang Qin
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical college of Soochow University, Suzhou, Jiangsu, China.
| | - Yun-Hong Li
- Department of Nutrition and Food Hygiene, School of Public Health, Suzhou Medical college of Soochow University, Suzhou, Jiangsu, China.
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Mao YJ, Ying MM, Xu G. Identification of hub genes and small molecule therapeutic drugs related to simple steatosis with secondary analysis of existing microarray data. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2114550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Yi-Jie Mao
- Department of Clinical Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou, People’s Republic of China
| | - Miao-Miao Ying
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
| | - Gang Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of China
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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 169] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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Zhou T, Kundu D, Robles-Linares J, Meadows V, Sato K, Baiocchi L, Ekser B, Glaser S, Alpini G, Francis H, Kennedy L. Feedback Signaling between Cholangiopathies, Ductular Reaction, and Non-Alcoholic Fatty Liver Disease. Cells 2021; 10:2072. [PMID: 34440841 PMCID: PMC8391272 DOI: 10.3390/cells10082072] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/03/2021] [Accepted: 08/04/2021] [Indexed: 12/12/2022] Open
Abstract
Fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), are global health disparities, particularly in the United States, as a result of cultural eating habits and lifestyle. Pathological studies on NAFLD have been mostly focused on hepatocytes and other inflammatory cell types; however, the impact of other biliary epithelial cells (i.e., cholangiocytes) in the promotion of NAFLD is growing. This review article will discuss how cholestatic injury and cholangiocyte activity/ductular reaction influence NAFLD progression. Furthermore, this review will provide informative details regarding the fundamental properties of cholangiocytes and bile acid signaling that can influence NAFLD. Lastly, studies relating to the pathogenesis of NAFLD, cholangiopathies, and ductular reaction will be analyzed to help gain insight for potential therapies.
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Affiliation(s)
- Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Jonathan Robles-Linares
- Department of Graduate Studies, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Keisaku Sato
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
| | - Leonardo Baiocchi
- Liver Unit, Department of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy;
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University, Indianapolis, IN 46202, USA;
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine Bryan, Bryan, TX 77807, USA;
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
- Richard L. Roudebush VA Medical Center, Department of Research, Indianapolis, IN 46202, USA
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
- Richard L. Roudebush VA Medical Center, Department of Research, Indianapolis, IN 46202, USA
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (T.Z.); (D.K.); (V.M.); (K.S.); (G.A.); (H.F.)
- Richard L. Roudebush VA Medical Center, Department of Research, Indianapolis, IN 46202, USA
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de Haan LR, Verheij J, van Golen RF, Horneffer-van der Sluis V, Lewis MR, Beuers UHW, van Gulik TM, Olde Damink SWM, Schaap FG, Heger M, Olthof PB. Unaltered Liver Regeneration in Post-Cholestatic Rats Treated with the FXR Agonist Obeticholic Acid. Biomolecules 2021; 11:biom11020260. [PMID: 33578971 PMCID: PMC7916678 DOI: 10.3390/biom11020260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/25/2021] [Accepted: 02/02/2021] [Indexed: 12/29/2022] Open
Abstract
In a previous study, obeticholic acid (OCA) increased liver growth before partial hepatectomy (PHx) in rats through the bile acid receptor farnesoid X-receptor (FXR). In that model, OCA was administered during obstructive cholestasis. However, patients normally undergo PHx several days after biliary drainage. The effects of OCA on liver regeneration were therefore studied in post-cholestatic Wistar rats. Rats underwent sham surgery or reversible bile duct ligation (rBDL), which was relieved after 7 days. PHx was performed one day after restoration of bile flow. Rats received 10 mg/kg OCA per day or were fed vehicle from restoration of bile flow until sacrifice 5 days after PHx. Liver regeneration was comparable between cholestatic and non-cholestatic livers in PHx-subjected rats, which paralleled liver regeneration a human validation cohort. OCA treatment induced ileal Fgf15 mRNA expression but did not enhance post-PHx hepatocyte proliferation through FXR/SHP signaling. OCA treatment neither increased mitosis rates nor recovery of liver weight after PHx but accelerated liver regrowth in rats that had not been subjected to rBDL. OCA did not increase biliary injury. Conclusively, OCA does not induce liver regeneration in post-cholestatic rats and does not exacerbate biliary damage that results from cholestasis. This study challenges the previously reported beneficial effects of OCA in liver regeneration in cholestatic rats.
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Affiliation(s)
- Lianne R. de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, China;
- Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (T.M.v.G.); (P.B.O.)
| | - Joanne Verheij
- Department of Pathology, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Rowan F. van Golen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;
| | - Verena Horneffer-van der Sluis
- National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; (V.H.-v.d.S.); (M.R.L.)
| | - Matthew R. Lewis
- National Phenome Centre, Department of Metabolism, Digestion and Reproduction, Imperial College London, London W12 0NN, UK; (V.H.-v.d.S.); (M.R.L.)
| | - Ulrich H. W. Beuers
- Department of Gastroenterology & Hepatology and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam UMC, Location AMC, 1105 AZ Amsterdam, The Netherlands;
| | - Thomas M. van Gulik
- Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (T.M.v.G.); (P.B.O.)
| | - Steven W. M. Olde Damink
- Department of Surgery & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands; (S.W.M.O.D.); (F.G.S.)
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Frank G. Schaap
- Department of Surgery & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands; (S.W.M.O.D.); (F.G.S.)
- Department of General, Visceral and Transplantation Surgery, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, China;
- Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (T.M.v.G.); (P.B.O.)
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands
- Correspondence: or ; Tel.: +86-138-19345926 or +31-30-2533966
| | - Pim B. Olthof
- Department of Surgery, Amsterdam UMC, Location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (T.M.v.G.); (P.B.O.)
- Department of Surgery, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands
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Ma Q, Chen J, Zhou X, Hu L, Sun Y, Wang Z, Yue Z, Shan A. Dietary supplementation with aromatic amino acids decreased triglycerides and alleviated hepatic steatosis by stimulating bile acid synthesis in mice. Food Funct 2021; 12:267-277. [PMID: 33300530 DOI: 10.1039/d0fo02364g] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Emerging evidence shows that amino acids can modulate lipid metabolism. Aromatic amino acids (AAAs) serve as important precursors of several neurotransmitters and metabolic regulators that play a vital role in regulating nutrient metabolism. But whether AAAs have a lipid-lowering function remains unknown. Here mice were fed amino acid-defined diets containing AAAs at 1.82% and 3.64% for 3 weeks. We demonstrated that double AAA intake significantly decreased the serum and hepatic triglycerides and serum low-density lipoprotein cholesterol, but increased the high-density lipoprotein cholesterol as well as insulin tolerance. Combined metabolomic and transcriptomic analysis showed that the hepatic acidic pathway of bile acid synthesis was responsible for the improvement in lipid metabolism by AAA treatment. This study suggests that AAAs have the potential to ameliorate steatosis and provides a new alternative to improve lipid metabolism.
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Affiliation(s)
- Qingquan Ma
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin, 150030, China.
| | - Jiayi Chen
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin, 150030, China.
| | - Xinbo Zhou
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin, 150030, China.
| | - Linlin Hu
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin, 150030, China.
| | - Yuchen Sun
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin, 150030, China.
| | - Zhishen Wang
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin, 150030, China.
| | - Zhiyuan Yue
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin, 150030, China.
| | - Anshan Shan
- Institute of Animal Nutrition, Northeast Agricultural University, Harbin, 150030, China.
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Xyloglucan affects gut-liver circulating bile acid metabolism to improve liver damage in mice fed with high-fat diet. J Funct Foods 2020. [DOI: 10.1016/j.jff.2019.103651] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
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iPla2β Deficiency Suppresses Hepatic ER UPR, Fxr, and Phospholipids in Mice Fed with MCD Diet, Resulting in Exacerbated Hepatic Bile Acids and Biliary Cell Proliferation. Cells 2019; 8:cells8080879. [PMID: 31409057 PMCID: PMC6721660 DOI: 10.3390/cells8080879] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 07/26/2019] [Accepted: 08/08/2019] [Indexed: 12/30/2022] Open
Abstract
Background: Group VIA calcium-independent phospholipase A2 (iPla2β) regulates homeostasis and remodeling of phospholipids (PL). We previously showed that iPla2β-/- mice fed with a methionine-choline-deficient diet (MCD) exhibited exaggerated liver fibrosis. As iPla2β is located in the endoplasmic reticulum (ER), we investigated the mechanisms for this by focusing on hepatic ER unfolded protein response (UPR), ER PL, and enterohepatic bile acids (BA). Methods: Female WT (wild-type) and iPla2β-/- mice were fed with chow or MCD for 5 weeks. PL and BA profiles were measured by liquid chromatography-mass spectrometry. Gene expression analyses were performed. Results: MCD feeding of WT mice caused a decrease of ER PL subclasses, which were further decreased by iPla2β deficiency. This deficiency alone or combined with MCD downregulated the expression of liver ER UPR proteins and farnesoid X-activated receptor. The downregulation under MCD was concomitant with an elevation of BA in the liver and peripheral blood and an increase of biliary epithelial cell proliferation measured by cytokeratin 19. Conclusion: iPla2β deficiency combined with MCD severely disturbed ER PL composition and caused inactivation of UPR, leading to downregulated Fxr, exacerbated BA, and ductular proliferation. Our study provides insights into iPla2β inactivation for injury susceptibility under normal conditions and liver fibrosis and cholangiopathies during MCD feeding.
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van Golen RF, Olthof PB, Lionarons DA, Reiniers MJ, Alles LK, Uz Z, de Haan L, Ergin B, de Waart DR, Maas A, Verheij J, Jansen PL, Damink SWO, Schaap FG, van Gulik TM, Heger M. FXR agonist obeticholic acid induces liver growth but exacerbates biliary injury in rats with obstructive cholestasis. Sci Rep 2018; 8:16529. [PMID: 30409980 PMCID: PMC6224438 DOI: 10.1038/s41598-018-33070-1] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 09/18/2018] [Indexed: 12/15/2022] Open
Abstract
Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree.
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Affiliation(s)
- Rowan F van Golen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Pim B Olthof
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Daniël A Lionarons
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Oncogene Biology Laboratory, The Francis Crick Institute and University College London, London, United Kingdom
| | - Megan J Reiniers
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Lindy K Alles
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Zehra Uz
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Lianne de Haan
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Bulent Ergin
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Dirk R de Waart
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Adrie Maas
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Joanne Verheij
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Peter L Jansen
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Steven W Olde Damink
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Frank G Schaap
- Department of Surgery, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Thomas M van Gulik
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Michal Heger
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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12
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Yan T, Wang H, Cao L, Wang Q, Takahashi S, Yagai T, Li G, Krausz KW, Wang G, Gonzalez FJ, Hao H. Glycyrrhizin Alleviates Nonalcoholic Steatohepatitis via Modulating Bile Acids and Meta-Inflammation. Drug Metab Dispos 2018; 46:1310-1319. [PMID: 29959134 PMCID: PMC6081736 DOI: 10.1124/dmd.118.082008] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 06/27/2018] [Indexed: 12/14/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is the progressive stage of nonalcoholic fatty liver disease that may ultimately lead to cirrhosis and liver cancer, and there are few therapeutic options for its treatment. Glycyrrhizin (GL), extracted from the traditional Chinese medicine liquorice, has potent hepatoprotective effects in both preclinical animal models and in humans. However, little is currently known about its effects and mechanisms in treating NASH. To explore the effects of GL on NASH, GL or its active metabolite glycyrrhetinic acid (GA) was administered to mice treated with a methionine- and choline-deficient (MCD) diet-induced NASH model, and histologic and biochemical analyses were used to measure the degree of lipid disruption, liver inflammation, and fibrosis. GL significantly improved MCD diet-induced hepatic steatosis, inflammation, and fibrosis and inhibited activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. GL significantly attenuated serum bile acid accumulation in MCD diet-fed mice partially by restoring inflammation-mediated hepatic farnesoid X receptor inhibition. In Raw 264.7 macrophage cells, both GL and GA inhibited deoxycholic acid-induced NLRP3 inflammasome-associated inflammation. Notably, both intraperitoneal injection of GL's active metabolite GA and oral administration of GL prevented NASH in mice, indicating that GL may attenuate NASH via its active metabolite GA. These results reveal that GL, via restoration of bile acid homeostasis and inhibition of inflammatory injury, can be a therapeutic option for treatment of NASH.
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Affiliation(s)
- Tingting Yan
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Hong Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Lijuan Cao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Qiong Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Shogo Takahashi
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Tomoki Yagai
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Guolin Li
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Kristopher W Krausz
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Guangji Wang
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Frank J Gonzalez
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
| | - Haiping Hao
- State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
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13
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van Golen RF, Olthof PB, de Haan LR, Coelen RJ, Pechlivanis A, de Keijzer MJ, Weijer R, de Waart DR, van Kuilenburg ABP, Roelofsen J, Gilijamse PW, Maas MA, Lewis MR, Nicholson JK, Verheij J, Heger M. The pathophysiology of human obstructive cholestasis is mimicked in cholestatic Gold Syrian hamsters. Biochim Biophys Acta Mol Basis Dis 2017; 1864:942-951. [PMID: 29196240 DOI: 10.1016/j.bbadis.2017.11.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Revised: 11/25/2017] [Accepted: 11/27/2017] [Indexed: 12/12/2022]
Abstract
Obstructive cholestasis causes liver injury via accumulation of toxic bile acids (BAs). Therapeutic options for cholestatic liver disease are limited, partially because the available murine disease models lack translational value. Profiling of time-related changes following bile duct ligation (BDL) in Gold Syrian hamsters revealed a biochemical response similar to cholestatic patients in terms of BA pool composition, alterations in hepatocyte BA transport and signaling, suppression of BA production, and adapted BA metabolism. Hamsters tolerated cholestasis well for up to 28days and progressed relatively slowly to fibrotic liver injury. Hepatocellular necrosis was absent, which coincided with preserved intrahepatic energy levels and only mild oxidative stress. The histological response to cholestasis in hamsters was similar to the changes seen in 17 patients with prolonged obstructive cholestasis caused by cholangiocarcinoma. Hamsters moreover upregulated hepatic fibroblast growth factor 15 (Fgf15) expression in response to BDL, which is a cytoprotective adaptation to cholestasis that hitherto had only been documented in cholestatic human livers. Hamster models should therefore be added to the repertoire of animal models used to study the pathophysiology of cholestatic liver disease.
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Affiliation(s)
- Rowan F van Golen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Pim B Olthof
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Lianne R de Haan
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Robert J Coelen
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Alexandros Pechlivanis
- Division of Computational, Systems and Digestive Medicine, Department of Surgery and Cancer, South Kensington Campus, London, SW7 2AZ, UK
| | - Mark J de Keijzer
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ruud Weijer
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Dirk R de Waart
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - André B P van Kuilenburg
- Laboratory Genetic Metabolic Disorders, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Jeroen Roelofsen
- Laboratory Genetic Metabolic Disorders, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Pim W Gilijamse
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Martinus A Maas
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Matthew R Lewis
- Division of Computational, Systems and Digestive Medicine, Department of Surgery and Cancer, South Kensington Campus, London, SW7 2AZ, UK; MRC-NIHR National Phenome Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK
| | - Jeremy K Nicholson
- Division of Computational, Systems and Digestive Medicine, Department of Surgery and Cancer, South Kensington Campus, London, SW7 2AZ, UK; MRC-NIHR National Phenome Centre, Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK
| | - Joanne Verheij
- Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Michal Heger
- Department of Experimental Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Membrane Biochemistry and Biophysics, Bijvoet Center for Biomolecular Research, Institute of Biomembranes, Utrecht University, Utrecht, The Netherlands.
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14
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Sommer J, Mahli A, Freese K, Schiergens TS, Kuecuekoktay FS, Teufel A, Thasler WE, Müller M, Bosserhoff AK, Hellerbrand C. Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice. Oncotarget 2017; 8:13059-13072. [PMID: 28055957 PMCID: PMC5355077 DOI: 10.18632/oncotarget.14371] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 12/05/2016] [Indexed: 12/27/2022] Open
Abstract
Chemotherapy-associated steatohepatitis is attracting increasing attention because it heralds an increased risk of morbidity and mortality in patients undergoing surgery because of liver metastases. The aim of this study was to develop in vitro and in vivo models to analyze the pathogenesis of 5-fluorouracil (5-FU)-induced steatohepatitis. Therefore, primary human hepatocytes and HepG2 hepatoma cells were incubated with 5-FU at non-toxic concentrations up to 24 h. Furthermore, hepatic tissue of C57BL/6N mice was analyzed 24 h after application of a single 5-FU dose (200 mg/kg body weight). In vitro, incubation with 5-FU induced a significant increase of hepatocellular triglyceride levels. This was paralleled by an impairment of mitochondrial function and a dose- and time-dependently increased expression of fatty acid acyl-CoA oxidase 1 (ACOX1), which catalyzes the initial step for peroxisomal β-oxidation. The latter is known to generate reactive oxygen species, and consequently, expression of the antioxidant enzyme heme oxygenase 1 (HMOX1) was significantly upregulated in 5-FU-treated cells, indicative for oxidative stress. Furthermore, 5-FU significantly induced c-Jun N-terminal kinase (JNK) activation and the expression of pro-inflammatory genes IL-8 and ICAM-1. Also in vivo, 5-FU significantly induced hepatic ACOX1 and HMOX1 expression as well as JNK-activation, pro-inflammatory gene expression and immune cell infiltration. In summary, we identified molecular mechanisms by which 5-FU induces hepatocellular lipid accumulation and inflammation. Our newly developed models can be used to gain further insight into the pathogenesis of 5-FU-induced steatohepatitis and to develop therapeutic strategies to inhibit its development and progression.
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Affiliation(s)
- Judith Sommer
- Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.,Department of Internal Medicine I, University Hospital Regensburg, Germany
| | - Abdo Mahli
- Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.,Department of Internal Medicine I, University Hospital Regensburg, Germany
| | - Kim Freese
- Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.,Department of Internal Medicine I, University Hospital Regensburg, Germany
| | - Tobias S Schiergens
- Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | | | - Andreas Teufel
- Department of Internal Medicine I, University Hospital Regensburg, Germany
| | - Wolfgang E Thasler
- Biobank o.b. HTCR, Department of General Visceral- and Transplantation Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Martina Müller
- Department of Internal Medicine I, University Hospital Regensburg, Germany
| | - Anja K Bosserhoff
- Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.,Comprehensive Cancer Center Erlangen, CCC Erlangen-EMN; Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Claus Hellerbrand
- Institute of Biochemistry (Emil-Fischer-Zentrum), Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.,Department of Internal Medicine I, University Hospital Regensburg, Germany
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