title: ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-α and PGC-1.
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.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Graz, Austria.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.forename: Tarek
authors.initials: T
authors.lastname: Moustafa
authors.forename: Gerald
authors.initials: G
authors.lastname: Woelkart
authors.forename: Sabrina
authors.initials: S
authors.lastname: Büttner
authors.forename: Albrecht
authors.initials: A
authors.lastname: Schmidt
authors.forename: Tineke
authors.initials: T
authors.lastname: van de Weijer
authors.forename: Matthijs
authors.initials: M
authors.lastname: Hesselink
authors.forename: Doris
authors.initials: D
authors.lastname: Jaeger
authors.forename: Petra C
authors.initials: PC
authors.lastname: Kienesberger
authors.forename: Kathrin
authors.initials: K
authors.lastname: Zierler
authors.forename: Renate
authors.initials: R
authors.lastname: Schreiber
authors.forename: Thomas
authors.initials: T
authors.lastname: Eichmann
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kolb
authors.forename: Petra
authors.initials: P
authors.lastname: Kotzbeck
authors.forename: Martina
authors.initials: M
authors.lastname: Schweiger
authors.forename: Manju
authors.initials: M
authors.lastname: Kumari
authors.forename: Sandra
authors.initials: S
authors.lastname: Eder
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schoiswohl
authors.forename: Nuttaporn
authors.initials: N
authors.lastname: Wongsiriroj
authors.forename: Nina M
authors.initials: NM
authors.lastname: Pollak
authors.forename: Franz P W
authors.initials: FP
authors.lastname: Radner
authors.forename: Karina
authors.initials: K
authors.lastname: Preiss-Landl
authors.forename: Thomas
authors.initials: T
authors.lastname: Kolbe
authors.forename: Thomas
authors.initials: T
authors.lastname: Rülicke
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinti
authors.forename: Erin E
authors.initials: EE
authors.lastname: Kershaw
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.forename: Frank
authors.initials: F
authors.lastname: Madeo
authors.forename: Bernd
authors.initials: B
authors.lastname: Mayer
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
mesh_terms: D000818:Animals; D015153:Blotting, Western; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics; D004452:Echocardiography; D005227:Fatty Acids / Q000378:metabolism*; D018628:Gene Dosage; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000502:physiology; D047493:PPAR alpha / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012508:Sarcolemma / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D004272:DNA, Mitochondrial; D005227:Fatty Acids; D008049:Lipase; D008156:Luciferases; D047493:PPAR alpha; D014157:Transcription Factors; D014280:Triglycerides; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases