title: Cardiac lipin 1 expression is regulated by the peroxisome proliferator activated receptor γ coactivator 1α/estrogen related receptor axis.
abstract: Lipin family proteins (lipin 1, 2, and 3) are bifunctional intracellular proteins that regulate metabolism by acting as coregulators of DNA-bound transcription factors and also dephosphorylate phosphatidate to form diacylglycerol [phosphatidate phosphohydrolase activity] in the triglyceride synthesis pathway. Herein, we report that lipin 1 is enriched in heart and that hearts of mice lacking lipin 1 (fld mice) exhibit accumulation of phosphatidate. We also demonstrate that the expression of the gene encoding lipin 1 (Lpin1) is under the control of the estrogen-related receptors (ERRs) and their coactivator the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). PGC-1α, ERRα, or ERRγ overexpression increased Lpin1 transcription in cultured ventricular myocytes and the ERRs were associated with response elements in the first intron of the Lpin1 gene. Concomitant RNAi-mediated knockdown of ERRα and ERRγ abrogated the induction of lipin 1 expression by PGC-1α overexpression. Consistent with these data, 3-fold overexpression of PGC-1α in intact myocardium of transgenic mice increased cardiac lipin 1 and ERRα/γ expression. Similarly, injection of the β2-adrenergic agonist clenbuterol induced PGC-1α and lipin 1 expression, and the induction in lipin 1 after clenbuterol occurred in a PGC-1α-dependent manner. In contrast, expression of PGC-1α, ERRα, ERRγ, and lipin 1 was down-regulated in failing heart. Cardiac phosphatidic acid phosphohydrolase activity was also diminished, while cardiac phosphatidate content was increased, in failing heart. Collectively, these data suggest that lipin 1 is the principal lipin protein in the myocardium and is regulated in response to physiologic and pathologic stimuli that impact cardiac metabolism.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Mayurranjan S
authors.initials: MS
authors.lastname: Mitra
authors.forename: Joel D
authors.initials: JD
authors.lastname: Schilling
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Wang
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Jay
authors.forename: Janice M
authors.initials: JM
authors.lastname: Huss
authors.forename: Xiong
authors.initials: X
authors.lastname: Su
authors.forename: Brian N
authors.initials: BN
authors.lastname: Finck
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D002976:Clenbuterol / Q000494:pharmacology; D004075:Diglycerides / Q000096:biosynthesis; D006333:Heart Failure / Q000378:metabolism; D007438:Introns; D013058:Mass Spectrometry; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase / Q000378:metabolism; D010712:Phosphatidic Acids / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D051381:Rats; D017207:Rats, Sprague-Dawley; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors; D014280:Triglycerides / Q000096:biosynthesis; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D002976:Clenbuterol; D004075:Diglycerides; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase; D010712:Phosphatidic Acids; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; D000097983:ERRalpha Estrogen-Related Receptor; C490916:Esrrg protein, mouse; C485290:Ppargc1a protein, mouse; C418978:Lpin1 protein, mouse