Role of mitochondria in nonalcoholic fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) affects about 30% of the general population in the United States and includes a spectrum of disease that includes simple steatosis, non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis. Significant insight has been gained into our understanding of the pathogenesis of NALFD; however the key metabolic aberrations underlying lipid accumulation in hepatocytes and the progression of NAFLD remain to be elucidated. Accumulating and emerging evidence indicate that hepatic mitochondria play a critical role in the development and pathogenesis of steatosis and NAFLD. Here, we review studies that document a link between the pathogenesis of NAFLD and hepatic mitochondrial dysfunction with particular focus on new insights into the role of impaired fatty acid oxidation, the transcription factor peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and sirtuins in development and progression of NAFLD.

Figure 1.

The “multiple parallel-hits” hypothesis of NAFLD: Insulin resistance leads to increased uptake and synthesis of FFAs in the liver, which sensitizes the liver to a series of hits causing liver injury and progression from simple steatosis to NASH [26].

Figure 2.

Hepatic β-oxidation: Mitochondrial β-oxidation involves four individual reactions (1–4) to generate NADH or FADH₂, which are then oxidized to H₂O by the mitochondrial respiratory chain. The mitochondrial respiratory chain consists of four respiratory complexes (I–IV) involved in the conversion of NADH and FADH₂ into oxidized cofactors NAD and FAD. Leakage of electrons at complexes I and II results in the formation of superoxide (O₂ ⁻) which is then transformed to H₂O₂ by superoxide dismutase (SOD1) in the intermediate space and by SOD₂ in the matrix to H₂O₂. Both H₂O₂ and O₂ ⁻ generated are reactive oxygen species (ROS). Mitochondrial antioxidant enzymes (SOD and glutathione peroxidase GPX) play a role in scavenging mitochondrial ROS. Adapted with permission from [61]. Copyright 1999–2014 John Wiley & Sons, Inc.)

Figure 3.

Role of the mitochondria in NAFLD. Impairment of mitochondrial function by genetic factors, aging, and overnutrition causes insulin resistance and mitochondrial dysfunction. Defective mitochondrial β-oxidation causes fatty liver and increases lipid toxic metabolites which may in turn causes insulin resistance, thus creating a vicious cycle between insulin resistance and mitochondrial dysfunction. Improved mitochondrial function by weight loss through caloric restriction and/or exercise improves insulin resistance. Regulators of mitochondrial biogenesis and function include genes such as peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and sirtuins. AMP-activated protein kinase (AMPK), fatty acid oxidation (FAO), mitochondrial respiratory chain (MRC), long chain fatty acid CoA (LCFA), Adenosine triphosphate (ATP), reactive oxygen species (ROS).