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 PKCε activity. Here, we report that nuclear estrogen-related receptor (ERR) γ is a novel transcriptional regulator of LIPIN1. Overexpression of ERRγ significantly increased LIPIN1 expression in primary hepatocytes, whereas the abolition of ERRγ gene expression attenuated the expression of LIPIN1. Deletion and mutation analyses of the LIPIN1 promoter showed that ERRγ 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 ERRγ is controlled by the competition between PGC-1α and small heterodimer partner. Additionally, ERRγ leads to the induction of hepatic LIPIN1 expression and diacylglycerol production in vivo. Finally, an inverse agonist of ERRγ, GSK5182, restores the impaired insulin signaling induced by LIPIN1-mediated PKCε activation. Our findings indicate that the selective control of ERRγ 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 PKCε activation.