2020 journal article
Branched chain amino acids and carbohydrate restriction exacerbate ketogenesis and hepatic mitochondrial oxidative dysfunction during NAFLD
FASEB Journal, 34(11), 14832–14849.
co-author countries:
United States of America 🇺🇸
Contributors: M. Muyyarikkandy *, M. McLeod *, M. Maguire *, R. Mahar *, N. Kattapuram *, C. Zhang *, C. Surugihalli*, V. Muralidaran*
author keywords: fatty liver; hepatic insulin resistance; lipogenesis; liver mitochondria
MeSH headings : Amino Acids, Branched-Chain / metabolism; Animals; Carbohydrate Metabolism; Citric Acid Cycle; Diet, Ketogenic / adverse effects; Lipogenesis; Liver / metabolism; Male; Mice; Mice, Inbred C57BL; Mitochondria, Liver / metabolism; Non-alcoholic Fatty Liver Disease / metabolism; Oxidative Stress
www.ncbi.nlm.nih.gov (repository)
Source: ORCID
Added: March 22, 2022
Mitochondrial adaptation during non-alcoholic fatty liver disease (NAFLD) include remodeling of flux and sustained tricarboxylic acid (TCA) cycle activity, which are concurrent to onset of oxidative stress. Over 70% of obese humans have NAFLD and diets are common weight loss strategies. However, the effectiveness of diets toward alleviating NAFLD remains unclear. We hypothesized that chronic ketogenesis will worsen metabolic dysfunction and oxidative stress during NAFLD. Mice (C57BL/6) were kept (for 16-wks) on either a low-fat, high-fat, or high-fat diet supplemented with 1.5X branched chain amino acids (BCAAs) by replacing carbohydrate calories (ketogenic). The diet induced hepatic lipid oxidation and ketogenesis, and produced multifaceted changes in flux through the individual steps of the TCA cycle. Higher rates of hepatic oxidative fluxes fueled by the diet paralleled lower rates of de novo lipogenesis. Interestingly, this metabolic remodeling did not improve insulin resistance, but induced fibrogenic genes and inflammation in the liver. Under a chronic ketogenic environment, the hepatocyte diverted more acetyl-CoA away from lipogenesis toward ketogenesis and TCA cycle, a milieu which can hasten oxidative stress and inflammation. In summary, chronic exposure to environment during obesity and NAFLD has the potential to aggravate hepatic mitochondrial dysfunction.
