Altered Mitochondrial Dynamics in Hepatocytes Induces Nonalcoholic Fatty Liver Disease Progression

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome that affects approximately 25% of adults globally. Although several pharmacological therapies have been reported to improve NAFLD, the therapeutic ranges of the drugs are limited. Mitochondrial dysfunction could be a key factor involved in NAFLD progression. However, the association between mitochondrial dynamics, which involves mitochondrial fission and fusion, and NAFLD development has not been fully characterized to date. Herein, we examined the effects of alterations of mitochondrial dynamics in hepatocytes and liver sinusoidal endothelial cells (LSECs), the most abundant non‐parenchymal cells in the liver, on NAFLD development and hypothesized that rebalancing of mitochondrial dynamics in these cells could attenuate NAFLD progression. Mice were fed a choline‐deficient, L‐amino acid‐defined diet (CDAA) for 1 or 4 weeks to recapitulate human NAFLD development. Malformed mitochondria, such as megamitochondria and mitochondria with deformed cristae, were substantially increased in both, hepatocytes and LSECs, of mice that were fed CDAA diet, and were associated with NAFLD development. In addition, decreased mitochondrial content and increased mitochondrial number, suggesting excessive mitochondrial fission, were induced in hepatocytes, but not in LSECs, after four weeks of CDAA feeding. These unfavorable changes in the mitochondria of hepatocytes, but not of LSECs, were attenuated by mdivi1, a chemical mitochondrial fission inhibitor. Liver inflammation and fibrosis were also attenuated by mdivi1, as assessed by serum biochemical and histochemical analyses. The expression of several inflammatory and fibrogenic genes (Tnfα, Il6, and Col3α1) tended to decrease with mdivi1 treatment. The expression of genes related to mitochondrial biogenesis, fission, fusion, and mitophagy was also significantly reduced by mdivi1 (p<0.05), suggesting rebalanced mitochondrial dynamics. Ultrastructural analyses revealed that endoplasmic reticulum stress and autophagy in hepatocytes were mitigated by mdivi1 administration. Taken together, these findings suggest that excessive mitochondrial fission in hepatocytes induces alterations in mitochondrial dynamics and other organellar injuries, and subsequently, liver inflammation and fibrogenesis. Therefore, rebalancing mitochondrial dynamics in hepatocytes by inhibiting excessive fission is a promising therapeutic strategy for NAFLD.