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Haemmerle, G.* ; Moustafa, T.* ; Woelkart, G.* ; Büttner, S.* ; Schmidt, A.* ; van de Weijer, T.* ; Hesselink, M.* ; Jaeger, D.* ; Kienesberger, P.C.* ; Zierler, K.* ; Schreiber, R.* ; Eichmann, T.* ; Kolb, D.* ; Kotzbeck, P. ; Schweiger, M.* ; Kumari, M.* ; Eder, S.* ; Schoiswohl, G.* ; Wongsiriroj, N.* ; Pollak, N.M.* ; Radner, F.P.* ; Preiss-Landl, K.* ; Kolbe, T.* ; Rülicke, T.* ; Pieske, B.* ; Trauner, M.* ; Lass, A.* ; Zimmermann, R.* ; Hoefler, G.* ; Cinti, S.* ; Kershaw, E.E.* ; Schrauwen, P.* ; Madeo, F.* ; Mayer, B.* ; Zechner, R.*

ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1.

J. Nat. Med. 17, 1076-1085 (2011)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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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Publication type Article: Journal article
Document type Scientific Article
ISSN (print) / ISBN 1340-3443
e-ISSN 1861-0293
Journal Journal of natural medicines
Quellenangaben Volume: 17, Issue: 9, Pages: 1076-1085 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Tokyo [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)