title: Estrogen-related receptor γ (ERRγ) is a novel transcriptional regulator of phosphatidic acid phosphatase, LIPIN1, and inhibits hepatic insulin signaling.
abstract: 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.
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Don-Kyu
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Department of Medicine, Gachon University of Medicine and Science, Incheon 406-840, Republic of Korea.
authors.forename: Jung Ran
authors.initials: JR
authors.lastname: Kim
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Minseob
authors.initials: M
authors.lastname: Koh
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Yong Deuk
authors.initials: YD
authors.lastname: Kim
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Ji-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chanda
authors.affiliation: Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea; Department of Biophysics and Chemical Biology, College of Natural Sciences, Seoul National University, Seoul 151-747, Republic of Korea.
authors.forename: Seung Bum
authors.initials: SB
authors.lastname: Park
authors.affiliation: Departments of Nuclear Medicine and Microbiology, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea; Bioimaging Research Center, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
authors.forename: Jung-Joon
authors.initials: JJ
authors.lastname: Min
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
authors.forename: Chul-Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Department of Medicine, Gachon University of Medicine and Science, Incheon 406-840, Republic of Korea.
authors.forename: Tae-Sik
authors.initials: TS
authors.lastname: Park
authors.affiliation: National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea; Research Institute of Medical Sciences, Department of Biomedical Sciences, Chonnam National University Medical School, Gwangju 501-746, Republic of Korea. Electronic address: hsc@chonnam.ac.kr.
authors.forename: Hueng-Sik
authors.initials: HS
authors.lastname: Choi
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000096:biosynthesis*; D010711:Phosphatidate Phosphatase / Q000096:biosynthesis / Q000235:genetics*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D007328:Insulin; D009687:Nuclear Proteins; D011960:Receptors, Estrogen; C425824:estrogen receptor gamma; D011493:Protein Kinase C; C485999:LPIN1 protein, human; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase