Lyall, M. J. | Search bioRxiv

bioRxiv2020

Nonalcoholic fatty liver disease is associated with decreased hepatocyte mitochondrial respiration but not mitochondrial number

Nonalcoholic fatty liver disease (NAFLD) is currently the most prevalent form of liver disease worldwide. This term covers a spectrum of pathologies, from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH). As the disease progresses, NASH can develop into cirrhosis and hepatocellular carcinoma. However, the underlying mechanisms and the factors which predispose an individual to disease progression remain poorly understood. Whilst NAFLD appears to be associated with mitochondrial dysfunction, it is unclear whether this is due to respiratory impairment, changes in mitochondrial mass, or mitochondrial fragmentation. Using a human pluripotent stem cell-based model of NAFLD we show that exposure to lactate, pyruvate and octanoic acid results in the development of macrovesicular steatosis. We do not observe changes in mitochondrial mass or fragmentation but do find decreases in maximal respiration and reserve capacity, suggesting impairment in the electron transport chain (ETC). Taken together, these findings indicate that the development of macrovesicular steatosis in NAFLD may be linked to the impairment of the ETC in mitochondria.

biochemistry↗

bioRxiv2017

Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD

Non-alcoholic fatty liver disease (NAFLD) is a global health issue. Dietary methyl donor restriction is used to induce a NAFLD/non-alcoholic steatohepatitis (NASH) phenotype in rodents, however the extent to which this model reflects human NAFLD remains incompletely understood. To address this, we undertook hepatic transcriptional profiling of methyl donor restricted rodents and compared these to published human NAFLD datasets.\n\nAdult C57BL/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for four weeks; the effects on methyl donor and lipid biology were investigated by bioinformatic analysis of hepatic gene expression profiles followed by a cross-species comparison with human expression data of all stages of NAFLD.\n\nCompared to controls, expression of the very low density lipoprotein (VLDL) packaging carboxylesterases (Ces1d, Ces1f, Ces3b) and the NAFLD risk allele Pnpla3 were suppressed in MCDD; with Pnpla3 and the liver predominant Ces isoform, Ces3b, also suppressed in CDD. With respect to 1-carbon metabolism, down-regulation of Chka, Chkb, Pcty1a, Gnmt and Ahcy with concurrent upregulation of Mat2a suggests a drive to maintain S-adenosylmethionine levels. There was minimal similarity between global gene expression patterns in either dietary intervention and any stage of human NAFLD, however some common transcriptomic changes in inflammatory, fibrotic and proliferative mediators were identified in MCDD, NASH and HCC.\n\nIn conclusion, this study suggests suppression of VLDL assembly machinery may contribute to hepatic lipid accumulation in these models, but that CDD and MCDD rodent diets are minimally representative of human NAFLD at the transcriptional level.\n\nSummary statementWe used transcriptional profiling of methyl donor restricted rodents to examine effects on methyl donor and lipid biology. We report novel mechanisms for lipid accumulation in this model and describe significant disparity between both dietary interventions and human disease.

molecular biology↗