期刊
NATURE MEDICINE
卷 17, 期 9, 页码 1076-U82出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2439
关键词
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资金
- GOLD - Genomics of Lipid-Associated Disorders
- Forschungsforderungsgesellschaft (FFG)
- Bundesministerium fur Wissenschaft und Forschung (BMWF)
- Spezialforschungsbereich (SFB [LIPOTOX F30]
- Doktoratskolleg: Molecular Enzymology [W901]
- Austrian Science Fund (FWF) [2007 Z136, P20602]
- Targeting Obesity-driven Inflammation (TOBI) [201608]
- LipidomicNet [202272]
- European Commission
- County of Styria
- City of Graz
- Netherlands Organization for Scientific Research [918.96.618]
- Center for Translational Molecular Medicine (CTMM) [01C-104]
- Netherlands Heart Foundation
- Dutch Diabetes Research Foundation
- Dutch Kidney Foundation
- Austrian Science Fund (FWF) [Z 136, W 901, F 3002, F 3008, F 3003] Funding Source: researchfish
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-1 alpha or PPAR-gamma coactivator-1 beta (PGC-1 alpha or PGC-1 beta, 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-1 alpha and PGC-1 beta 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.
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