Estrogen-related Receptor γ (ERRγ) Is a Novel Transcriptional Regulator of Phosphatidic Acid Phosphatase, LIPIN1, and Inhibits Hepatic Insulin Signaling

LIPINs have been reported to perform important roles in the regulation of intracellular lipid levels. Their mutations induce lipodystrophy, myoglobinuria, and inflammatory disorders. Recently, the phosphatidic acid phosphatase function of LIPINs has been associated with the perturbation of hepatic insulin receptor signaling via the diacylglycerol-mediated stimulation of PKC epsilon activity. Here, we report that nuclear estrogen-related receptor (ERR) gamma is a novel transcriptional regulator of LIPIN1. Overexpression of ERR gamma significantly increased LIPIN1 expression in primary hepatocytes, whereas the abolition of ERR gamma gene expression attenuated the expression of LIPIN1. Deletion and mutation analyses of the LIPIN1 promoter showed that ERR gamma exerts its effect on the transcriptional regulation of LIPIN1 via ERRE1 of the LIPIN1 promoter, as confirmed by ChIP assay. We also determined that the gene transcription of LIPIN1 by ERR gamma is controlled by the competition between PGC-1 alpha and small heterodimer partner. Additionally, ERR gamma leads to the induction of hepatic LIPIN1 expression and diacylglycerol production in vivo. Finally, an inverse agonist of ERR gamma, GSK5182, restores the impaired insulin signaling induced by LIPIN1-mediated PKC epsilon activation. Our findings indicate that the selective control of ERR gamma transcriptional activity by its specific inverse agonist could provide a novel therapeutic approach to the amelioration of impaired hepatic insulin signaling induced by LIPIN1-mediated PKC epsilon activation.