Liver-specific deletion of RORα aggravates diet-induced nonalcoholic steatohepatitis by inducing mitochondrial dysfunction

초록

Mitochondrial dysfunction may play a key role in the progression of steatosis to nonalcoholic steatohepatitis (NASH); however, the molecular mechanism that controls the structure and function of mitochondria in NASH is not clearly understood. Here, we demonstrated that ROR alpha is a regulator of expression of Bnip3 and PGC-1 alpha, and thereby enhances mitochondrial quality. First, we observed that liver-specific ROR alpha knockout mice (ROR alpha-LKO) were more susceptible to high-fat diet-induced NASH compared with control, probably due to mitochondrial dysfunction. Concordantly, mitochondrial fission in response to nutrient stimuli was abolished with downregulation of Bnip3 and phospho-Drp1 in the hepatocytes of ROR alpha-LKO. ROR alpha enhanced oxygen consumption rate and expression of genes associated with mitochondrial quality control. Finally, we observed the positive correlation of the expression levels of Bnip3 and PGC-1 alpha with those of ROR alpha in patients with steatohepatitis. Together, we demonstrated that ROR alpha mediates mitochondrial quality under nutrient-overloaded conditions and propose ROR alpha as a potential therapeutic target in treatment of NASH.

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