| First Author | Haemmerle G | Year | 2011 |
| Journal | Nat Med | Volume | 17 |
| Issue | 9 | Pages | 1076-85 |
| PubMed ID | 21857651 | Mgi Jnum | J:176252 |
| Mgi Id | MGI:5289758 | Doi | 10.1038/nm.2439 |
| Citation | Haemmerle G, et al. (2011) ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat Med 17(9):1076-85 |
| abstractText | 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. |
