TY - JOUR
T1 - Cardiac lipin 1 expression is regulated by the peroxisome proliferator activated receptor γ coactivator 1α/estrogen related receptor axis
AU - Mitra, Mayurranjan S.
AU - Schilling, Joel D.
AU - Wang, Xiaowei
AU - Jay, Patrick Y.
AU - Huss, Janice M.
AU - Su, Xiong
AU - Finck, Brian N.
N1 - Funding Information:
We thank Dr. K. Reue for the gift of lipin 1 promoter plasmids, Dr. A. Kralli for the ERRγ shRNA, and Dr. D. Kelly for the gift of PGC-1α-deficient and overexpressing mice. The alpha-tubulin monoclonal antibody developed by Dr. C. Walsh was obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biology, Iowa City,IA 52242. This work was supported by the NIH grants R01 DK78187 (to B.N.F) and R01 DK74700 (to J.M.H.). P.Y.J is a Scholar of the Child Health Research Center of Excellence in Developmental Biology at Washington University School of Medicine (K12-HD001487). X. S. is supported by a Scientist Development Grant from the American Heart Association ( 835140N ). This work was also supported by the cores of the Nutrition Obesity Research Center ( P30 DK56341 ).
PY - 2011/7
Y1 - 2011/7
N2 - 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, or 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, or 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.
AB - 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, or 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, or 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.
KW - Estrogen Related Receptors
KW - Heart failure
KW - Lipin
KW - Metabolism
KW - PGC-1α
KW - Phosphatidic Acid
UR - http://www.scopus.com/inward/record.url?scp=79956293920&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2011.04.009
DO - 10.1016/j.yjmcc.2011.04.009
M3 - Article
C2 - 21549711
AN - SCOPUS:79956293920
VL - 51
SP - 120
EP - 128
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
SN - 0022-2828
IS - 1
ER -