ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1
Guenter Haemmerle,Tarek Moustafa,Gerald Woelkart,Sabrina Büttner,Albrecht Schmidt,Tineke van de Weijer,Matthijs K. C. Hesselink,Doris Jaeger,Petra C. Kienesberger,Kathrin A. Zierler,Renate Schreiber,Thomas O. Eichmann,Dagmar Kolb,Petra Kotzbeck,Martina Schweiger,Manju Kumari,Sandra Eder,Gabriele Schoiswohl,Nuttaporn Wongsiriroj,Nina M. Pollak,Franz P.W. Radner,Karina Preiss-Landl,Thomas Kolbe,Thomas Rülicke,Burkert Pieske,Michael Trauner,Achim Lass,Robert Zimmermann,Gerald Hoefler,Saverio Cinti,Erin E. Kershaw,Patrick Schrauwen,Frank Madeo,Bernd Mayer,Rudolf Zechner +34 more
TL;DR: 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.
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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.
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