Cardiac lipin 1 expression is regulated by the peroxisome proliferator activated receptor ? coactivator 1?/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 ? coactivator-1? (PGC-1?). PGC-1?, ERR?, or ERR? 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? and ERR? abrogated the induction of lipin 1 expression by PGC-1? overexpression. Consistent with these data, 3-fold overexpression of PGC-1? in intact myocardium of transgenic mice increased cardiac lipin 1 and ERR?/? expression. Similarly, injection of the ?2-adrenergic agonist clenbuterol induced PGC-1? and lipin 1 expression, and the induction in lipin 1 after clenbuterol occurred in a PGC-1?-dependent manner. In contrast, expression of PGC-1?, ERR?, ERR?, 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.

SUBMITTER: Mitra MS 

PROVIDER: S-EPMC3104300 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature