RORα regulates hepatic lipolysis by inducing transcriptional expression of PNPLA3 in mice

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 α (RORα) regulates various target genes related to lipid metabolism. Here, we investigated the role of RORα on PNPLA3-mediated hepatic lipid hydrolysis. With blockade of lipid esterification and β-oxidation, RORα enhanced TAG hydrolysis, resulting in increased free glycerol levels. We found a putative RORα response element on the upstream of PNPLA3 gene that was activated by RORα. Furthermore, the inhibitory action of cJUN on the RORα/PNPLA3 axis was enhanced under lipid stress and contributed to hepatic lipid accumulation. In summary, we showed for the first time that RORα activates the transcription of PNPLA3, which suggests that RORα and its ligands represent potential precision therapeutic approaches for NAFLDs.