Han_2020_Mol.Cell.Endocrinol__111122

Nonalcoholic fatty liver diseases (NAFLDs) are characterized by excessive triacylglycerol (TAG) accumulation in the liver which contributes to hepatocyte dysfunction, inflammation, and fibrosis. Patatin-like phospholipase domain-containing 3 (PNPLA3; also known as adiponutrin) has emerged as an important enzyme leading to hepatic TAG hydrolysis. Because the I148M substitution in the PNPLA3 gene markedly reduces hepatic TAG hydrolase activity, this genetic variation is strongly associated with increased hepatic TAG in the full spectrum of NAFLDs. The Retinoic acid-related orphan receptor alpha (RORalpha) regulates various target genes related to lipid metabolism. Here, we investigated the role of RORalpha on PNPLA3-mediated hepatic lipid hydrolysis. With blockade of lipid esterification and beta-oxidation, RORalpha enhanced TAG hydrolysis, resulting in increased free glycerol levels. We found a putative RORalpha response element on the upstream of PNPLA3 gene that was activated by RORalpha. Furthermore, the inhibitory action of cJUN on the RORalpha/PNPLA3 axis was enhanced under lipid stress and contributed to hepatic lipid accumulation. In summary, we showed for the first time that RORalpha activates the transcription of PNPLA3, which suggests that RORalpha and its ligands represent potential precision therapeutic approaches for NAFLDs.