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Cardiac lipin 1 expression is regulated by the peroxisome proliferator activated receptor γ coactivator 1α/estrogen related receptor axis.
J Mol Cell Cardiol. 2011 Jul; 51(1):120-8.JM

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+Show Affiliations

Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21549711

Citation

Mitra, Mayurranjan S., et al. "Cardiac Lipin 1 Expression Is Regulated By the Peroxisome Proliferator Activated Receptor Γ Coactivator 1α/estrogen Related Receptor Axis." Journal of Molecular and Cellular Cardiology, vol. 51, no. 1, 2011, pp. 120-8.
Mitra MS, Schilling JD, Wang X, et al. Cardiac lipin 1 expression is regulated by the peroxisome proliferator activated receptor γ coactivator 1α/estrogen related receptor axis. J Mol Cell Cardiol. 2011;51(1):120-8.
Mitra, M. S., Schilling, J. D., Wang, X., Jay, P. Y., Huss, J. M., Su, X., & Finck, B. N. (2011). Cardiac lipin 1 expression is regulated by the peroxisome proliferator activated receptor γ coactivator 1α/estrogen related receptor axis. Journal of Molecular and Cellular Cardiology, 51(1), 120-8. https://doi.org/10.1016/j.yjmcc.2011.04.009
Mitra MS, et al. Cardiac Lipin 1 Expression Is Regulated By the Peroxisome Proliferator Activated Receptor Γ Coactivator 1α/estrogen Related Receptor Axis. J Mol Cell Cardiol. 2011;51(1):120-8. PubMed PMID: 21549711.
* Article titles in AMA citation format should be in sentence-case
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, Y1 - 2011/04/28/ PY - 2011/03/24/received PY - 2011/04/15/revised PY - 2011/04/19/accepted PY - 2011/5/10/entrez PY - 2011/5/10/pubmed PY - 2011/9/15/medline SP - 120 EP - 8 JF - Journal of molecular and cellular cardiology JO - J. Mol. Cell. Cardiol. VL - 51 IS - 1 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 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. SN - 1095-8584 UR - https://www.unboundmedicine.com/medline/citation/21549711/Cardiac_lipin_1_expression_is_regulated_by_the_peroxisome_proliferator_activated_receptor_γ_coactivator_1α/estrogen_related_receptor_axis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-2828(11)00166-0 DB - PRIME DP - Unbound Medicine ER -