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

초록

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

키워드