ATGL-mediated Fat Catabolism Regulates Cardiac Mitochondrial Function via PPAR-α and PGC-1

Nat Med. 2011 Aug 21;17(9):1076-85. doi: 10.1038/nm.2439.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cardiomyopathies / etiology
  • Cardiomyopathies / metabolism*
  • DNA Primers / genetics
  • DNA, Complementary / genetics
  • DNA, Mitochondrial / genetics
  • Echocardiography
  • Fatty Acids / metabolism*
  • Gene Dosage
  • Lipase / genetics
  • Lipase / metabolism*
  • Luciferases
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron, Transmission
  • Mitochondria / physiology*
  • Myocytes, Cardiac / physiology
  • Oxidation-Reduction
  • Oxygen Consumption / physiology
  • PPAR alpha / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sarcolemma / physiology
  • Transcription Factors / metabolism*
  • Triglycerides / metabolism*

Substances

  • DNA Primers
  • DNA, Complementary
  • DNA, Mitochondrial
  • Fatty Acids
  • PPAR alpha
  • Transcription Factors
  • Triglycerides
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Luciferases
  • Lipase
  • PNPLA2 protein, mouse