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-γ coactivator-1α or PPAR-γ coactivator-1β (PGC-1α or PGC-1β, 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-α and PPAR-δ target genes. In the heart, this leads to decreased PGC-1α and PGC-1β 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-α 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.
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This research was supported by the following grants: GOLD - Genomics of Lipid-Associated Disorders as part of the Austrian Genome Project (GEN-AU) funded by the Forschungsförderungsgesellschaft (FFG) and the Bundesministerium für Wissenschaft und Forschung (BMWF); Spezialforschungsbereich (SFB) LIPOTOX F30, Doktoratskolleg: Molecular Enzymology W901, the Wittgenstein Award 2007 Z136 and research grant P20602 funded by the Austrian Science Fund (FWF); Targeting Obesity-driven Inflammation (TOBI) contract no. 201608 and LipidomicNet contract no. 202272 funded by the European Commission. Additional funding for the SFB LIPOTOX was granted by the County of Styria and the City of Graz. P.S. is supported by the Research Grant for Innovative Research from the Netherlands Organization for Scientific Research (Grant 918.96.618). T.v.d.W. was supported by the Center for Translational Molecular Medicine (CTMM) project PREDICCt (Grant 01C-104) and the Netherlands Heart Foundation, the Dutch Diabetes Research Foundation and the Dutch Kidney Foundation. We thank E. Zechner and C. Schober-Trummler for proofreading the manuscript and S. Lang for the preparation of the cartoon. The pBS II SK+ vector containing the α-MHC promoter region (Genbank: U71441) was provided by J. Robbins (University of Cincinnati). The expression plasmids for (PPRE)6-tk-luciferase and human PPAR-α were provided by B. Staels (University of Lille).
The authors declare no competing financial interests.
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Haemmerle, G., Moustafa, T., Woelkart, G. et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1. Nat Med 17, 1076–1085 (2011). https://doi.org/10.1038/nm.2439
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