학술논문
ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-? and PGC-1.
Document Type
Article
Author
Haemmerle, Guenter; Moustafa, Tarek; Woelkart, Gerald; Büttner, Sabrina; Schmidt, Albrecht; van de Weijer, Tineke; Hesselink, Matthijs; Jaeger, Doris; Kienesberger, Petra C; Zierler, Kathrin; Schreiber, Renate; Eichmann, Thomas; Kolb, Dagmar; Kotzbeck, Petra; Schweiger, Martina; Kumari, Manju; Eder, Sandra; Schoiswohl, Gabriele; Wongsiriroj, Nuttaporn; Pollak, Nina M
Source
Subject
*METABOLISM
*PEROXISOMES
*HORMONE receptors
*TRIGLYCERIDES
*CARDIOMYOPATHIES
*
*
*
*
Language
ISSN
1078-8956
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-? coactivator-1? or PPAR-? coactivator-1? (PGC-1? or PGC-1?, 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-? and PPAR-? target genes. In the heart, this leads to decreased PGC-1? and PGC-1? 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-? 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. [ABSTRACT FROM AUTHOR]