ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1

G. Haemmerle, T. Moustafa, G. Woelkart, S. Buttner, A. Schmidt, T. van de Weijer, M.K.C. Hesselink, D. Jaeger, P.C. Kienesberger, K. Zierler, R. Schreiber, T. Eichmann, D. Kolb, P. Kotzbeck, M. Schweiger, M. Kumari, S. Eder, G. Schoiswohl, N. Wongsiriroj, N.M. PollakF.P. Radner, K. Preiss Landl, T. Kolbe, T. Rulicke, B. Pieske, M. Trauner, A. Lass, R. Zimmermann, G. Hoefler, S. Cinti, E.E. Kershaw, P. Schrauwen, F. Madeo, B. Mayer, R. Zechner

Research output: Contribution to journalArticleAcademicpeer-review

256 Citations (Scopus)

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate genes involved in energy metabolism and inflammation. For biological activity, PPARs require cognate lipid ligands, heterodimerization with retinoic X receptors, and coactivation by PPAR-gamma coactivator-1alpha or PPAR-gamma coactivator-1beta (PGC-1alpha or PGC-1beta, encoded by Ppargc1a and Ppargc1b, respectively). Here we show that lipolysis of cellular triglycerides by adipose triglyceride lipase (patatin-like phospholipase domain containing protein 2, encoded by Pnpla2; hereafter referred to as Atgl) generates essential mediator(s) involved in the generation of lipid ligands for PPAR activation. Atgl deficiency in mice decreases mRNA levels of PPAR-alpha and PPAR-delta target genes. In the heart, this leads to decreased PGC-1alpha and PGC-1beta expression and severely disrupted mitochondrial substrate oxidation and respiration; this is followed by excessive lipid accumulation, cardiac insufficiency and lethal cardiomyopathy. Reconstituting normal PPAR target gene expression by pharmacological treatment of Atgl-deficient mice with PPAR-alpha agonists completely reverses the mitochondrial defects, restores normal heart function and prevents premature death. These findings reveal a potential treatment for the excessive cardiac lipid accumulation and often-lethal cardiomyopathy in people with neutral lipid storage disease, a disease marked by reduced or absent ATGL activity.
Original languageEnglish
Pages (from-to)1076-1085
Number of pages13
JournalNature Medicine
Volume17
Issue number9
DOIs
Publication statusPublished - Sep 2011

Keywords

  • PROLIFERATOR-ACTIVATED RECEPTORS
  • HORMONE-SENSITIVE LIPASE
  • LIPID STORAGE DISEASE
  • ACID-METABOLIZING ENZYMES
  • TRIGLYCERIDE LIPASE
  • ENERGY-METABOLISM
  • HYPOLIPIDEMIC DRUGS
  • INSULIN SENSITIVITY
  • GENE-EXPRESSION
  • TRANSGENIC MICE

Cite this

Haemmerle, G., Moustafa, T., Woelkart, G., Buttner, S., Schmidt, A., van de Weijer, T., Hesselink, M. K. C., Jaeger, D., Kienesberger, P. C., Zierler, K., Schreiber, R., Eichmann, T., Kolb, D., Kotzbeck, P., Schweiger, M., Kumari, M., Eder, S., Schoiswohl, G., Wongsiriroj, N., ... Zechner, R. (2011). ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nature Medicine, 17(9), 1076-1085. https://doi.org/10.1038/nm.2439