title: Dietary cholesterol induces hepatic inflammation and blunts mitochondrial function in the liver of high-fat-fed mice.
abstract: The present study investigated the role of dietary cholesterol and fat in the development of nonalcoholic fatty liver disease, a common liver disease in metabolic disorders. Mice were fed a diet of regular chow (CH), chow supplemented with 0.2% w/w cholesterol (CHC), high fat (HF, 45kcal%) or HF with cholesterol (HFC) for 17weeks. While both HF and HFC groups displayed hepatic steatosis and metabolic syndrome, only HFC group developed the phenotype of liver injury, as indicated by an increase in plasma level of alanine transaminase (ALT, by 50-80%). There were ~2-fold increases in mRNA expression of tumor necrosis factor α, interleukin 1β and monocyte chemotactic protein 1 in the liver of HFC-fed mice (vs. HF) but no endoplasmic reticulum stress or oxidative stress was observed. Furthermore, cholesterol suppressed HF-induced increase of peroxisome proliferator-activated receptor γ coactivator 1α and mitochondrial transcription factor A expression and blunted fatty acid oxidation. Interestingly, after switching HFC to HF diet for 5weeks, the increases in plasma ALT and liver inflammatory markers were abolished but the blunted of mitochondrial function remained. These findings suggest that cholesterol plays a critical role in the conversion of a simple fatty liver toward nonalcoholic steatohepatitis possibly by activation of inflammatory pathways together with retarded mitochondrial function.
authors.affiliation: Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Songpei
authors.initials: S
authors.lastname: Li
authors.affiliation: Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Zeng
authors.affiliation: Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Xiu
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Jo
authors.affiliation: Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Robinson
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and Department of Medicine, the University of Hong Kong, Hong Kong, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
authors.affiliation: Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia. Electronic address: jiming.ye@rmit.edu.au.
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
mesh_terms: D000818:Animals; D002791:Cholesterol, Dietary; D059305:Diet, High-Fat; D051379:Mice; D008930:Mitochondria, Liver / Q000502:physiology*; D065626:Non-alcoholic Fatty Liver Disease / Q000503:physiopathology*; D010084:Oxidation-Reduction
chemical_list: D002791:Cholesterol, Dietary
keywords: Dietary cholesterol; High fat diet; Inflammation; Mitochondrial function; Nonalcoholic fatty liver disease