ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-Î ± and PGC-1

G Haemmerle; T Moustafa; G Woelkart; S Büttner; A Schmidt; T Van De Weijer; M Hesselink; D Jaeger; P C Kienesberger; K Zierler; R Schreiber; T Eichmann; D Kolb; P Kotzbeck; M Schweiger; M Kumari; S Eder; G Schoiswohl; N Wongsiriroj; Nina M Pollak; Franz P W Radner; Karina Preiss-Landl; Thomas Kolbe; Thomas Rulicke; Burkert Pieske; Michael Trauner; Achim Lass; Robert Zimmermann; Gerald Hoefler; Saverio Cinti; Erin E Kershaw; Patrick Schauwen; Frank Madeo; Bernd Mayer; Rudolf Zechner

doi:10.1038/nm.2439

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ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-Î ± and PGC-1

Journal article

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ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-Î ± and PGC-1

G Haemmerle, T Moustafa, G Woelkart, S Büttner, A Schmidt, T Van De Weijer, M Hesselink, D Jaeger, P C Kienesberger, K Zierler, …

Nature Medicine, Vol.17(9), pp.1076-1085

2011

DOI: https://doi.org/10.1038/nm.2439

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Abstract

cardiomyopathies

cardiovascular biology

fat metabolism

metabolic disorders

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. © 2011 Nature America, Inc. All rights reserved.

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Title: ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-Î ± and PGC-1
Authors: G Haemmerle (Author) - University of Graz, Austria
T Moustafa (Author) - University of Graz, Austria
G Woelkart (Author) - University of Graz, Austria
S Büttner (Author) - University of Graz, Austria
A Schmidt (Author) - University of Graz, Austria
T Van De Weijer (Author) - Maastricht University Medical Centre, Netherlands
M Hesselink (Author) - Maastricht University Medical Centre, Netherlands
D Jaeger (Author) - University of Graz, Austria
P C Kienesberger (Author) - University of Graz, Austria
K Zierler (Author) - University of Graz, Austria
R Schreiber (Author) - University of Graz, Austria
T Eichmann (Author) - University of Graz, Austria
D Kolb (Author) - Maastricht University Medical Centre, Netherlands
P Kotzbeck (Author) - University of Graz, Austria
M Schweiger (Author) - University of Graz, Austria
M Kumari (Author) - University of Graz, Austria
S Eder (Author) - University of Graz, Austria
G Schoiswohl (Author) - University of Graz, Austria
N Wongsiriroj (Author) - University of Graz, Austria
Nina M Pollak (Author) - University of Graz, Austria
Franz P W Radner (Author) - University of Graz, Austria
Karina Preiss-Landl (Author) - University of Graz, Austria
Thomas Kolbe (Author) - Maastricht University Medical Centre, Netherlands
Thomas Rulicke (Author) - University of Veterinary Medicine, Austria
Burkert Pieske (Author) - Medical University of Graz, Austria
Michael Trauner (Author) - University of Graz, Austria
Achim Lass (Author) - University of Graz, Austria
Robert Zimmermann (Author) - University of Graz, Austria
Gerald Hoefler (Author) - Medical University of Graz, Austria
Saverio Cinti (Author) - University of Ancona, Italy
Erin E Kershaw (Author) - University of Pittsburgh, United States
Patrick Schauwen (Author) - Maastricht University Medical Centre, Netherlands
Frank Madeo (Author) - University of Graz, Austria
Bernd Mayer (Author) - University of Graz, Austria
Rudolf Zechner (Author) - University of Graz, Austria
Publication details: Nature Medicine, Vol.17(9), pp.1076-1085
Publisher: Nature Publishing Group
Date published: 2011
DOI: 10.1038/nm.2439
ISSN: 1078-8956
Copyright note: Copyright © 2011 Nature Publishing Group. The accepted version is reproduced here in accordance with the publishers copyright policy. The definitive version is available from http://www.nature.com/icb/
Organisation Unit: School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99450916502621
Output Type: Journal article

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