Cardiac lipin 1 expression is regulated by the peroxisome proliferator activated receptor γ coactivator 1α/estrogen related receptor axis

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 115 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 gamma coactivator-1 alpha (PGC-1 alpha). PGC-1 alpha, ERR alpha, or ERR gamma 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 ERR alpha and ERR gamma abrogated the induction of lipin 1 expression by PGC-1 alpha overexpression. Consistent with these data, 3-fold overexpression of PGC-1 alpha in intact myocardium of transgenic mice increased cardiac lipin 1 and ERR beta/gamma expression. Similarly, injection of the beta 2-adrenergic agonist clenbuterol induced PGC-la and lipin 1 expression, and the induction in lipin 1 after clenbuterol occurred in a PGC-1 alpha-dependent manner. In contrast, expression of PGC-1 alpha, ERR alpha, ERR gamma, 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. (C) 2011 Elsevier Ltd. All rights reserved.