Mitochondrial Adaptation in Nonalcoholic Fatty Liver Disease: Novel Mechanisms and Treatment Strategies

Trends Endocrinol Metab. 2017 Apr;28(4):250-260. doi: 10.1016/j.tem.2016.11.006. Epub 2016 Dec 13.


Nonalcoholic fatty liver disease (NAFLD) is prevalent in patients with obesity or type 2 diabetes. Nonalcoholic steatohepatitis (NASH), encompassing steatosis with inflammation, hepatocyte injury, and fibrosis, predisposes to cirrhosis, hepatocellular carcinoma, and even cardiovascular disease. In rodent models and humans with NAFLD/NASH, maladaptation of mitochondrial oxidative flux is a central feature of simple steatosis to NASH transition. Induction of hepatic tricarboxylic acid cycle closely mirrors the severity of oxidative stress and inflammation in NASH. Reactive oxygen species generation and inflammation are driven by upregulated, but inefficient oxidative flux and accumulating lipotoxic intermediates. Successful therapies for NASH (weight loss alone or with incretin therapy, or pioglitazone) likely attenuate mitochondrial oxidative flux and halt hepatocellular injury. Agents targeting mitochondrial dysfunction may provide a novel treatment strategy for NAFLD.

Keywords: diabetes; fatty liver; glucagon-like peptide-1; mitochondria; nonalcoholic steatohepatitis; obesity; pioglitazone.

Publication types

  • Review

MeSH terms

  • Animals
  • Fatty Liver / drug therapy
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fatty Liver / therapy
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Mitochondria / metabolism*
  • Mitochondria / pathology*
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / metabolism*
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Non-alcoholic Fatty Liver Disease / therapy
  • Obesity / drug therapy
  • Obesity / metabolism
  • Obesity / pathology
  • Obesity / therapy
  • Pioglitazone
  • Thiazolidinediones / therapeutic use


  • Thiazolidinediones
  • Glucagon-Like Peptide 1
  • Pioglitazone