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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Haemmerle, G; Moustafa, T; Woelkart, G; Büttner, S; Schmidt, A; van, de, Weijer, T; Hesselink, M; Jaeger, D; Kienesberger, PC; Zierler, K; Schreiber, R; Eichmann, T; Kolb, D; Kotzbeck, P; Schweiger, M; Kumari, M; Eder, S; Schoiswohl, G; Wongsiriroj, N; Pollak, NM; Radner, FP; Preiss-Landl, K; Kolbe, T; Rülicke, T; Pieske, B; Trauner, M; Lass, A; Zimmermann, R; Hoefler, G; Cinti, S; Kershaw, EE; Schrauwen, P; Madeo, F; Mayer, B; Zechner, R.
ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1.
Nat Med. 2011; 17(9):1076-85
Doi: 10.1038/nm.2439
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- Co-Autor*innen der Med Uni Graz
- Eichmann Thomas
- Höfler Gerald
- Kolb Dagmar
- Kotzbeck Petra
- Moustafa Tarek
- Pieske Burkert Mathias
- Schmidt Albrecht
- Schoiswohl Gabriele Maria
- Schreiber Renate
- Trauner Michael
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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.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals - administration & dosage
- Blotting, Western - administration & dosage
- Cardiomyopathies - etiology, metabolism
- DNA Primers - genetics
- DNA, Complementary - genetics
- DNA, Mitochondrial - genetics
- Echocardiography - administration & dosage
- Fatty Acids - metabolism
- Gene Dosage - administration & dosage
- Lipase - genetics, metabolism
- Luciferases - administration & dosage
- Mice - administration & dosage
- Mice, Inbred C57BL - administration & dosage
- Mice, Knockout - administration & dosage
- Microscopy, Electron, Transmission - administration & dosage
- Mitochondria - physiology
- Myocytes, Cardiac - physiology
- Oxidation-Reduction - administration & dosage
- Oxygen Consumption - physiology
- PPAR alpha - metabolism
- Reverse Transcriptase Polymerase Chain Reaction - administration & dosage
- Sarcolemma - physiology
- Transcription Factors - metabolism
- Triglycerides - metabolism