Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Kolleritsch, S; Kien, B; Schoiswohl, G; Diwoky, C; Schreiber, R; Heier, C; Maresch, LK; Schweiger, M; Eichmann, TO; Stryeck, S; Krenn, P; Tomin, T; Schittmayer, M; Kolb, D; Rülicke, T; Hoefler, G; Wolinski, H; Madl, T; Birner-Gruenberger, R; Haemmerle, G.
Low cardiac lipolysis reduces mitochondrial fission and prevents lipotoxic heart dysfunction in Perilipin 5 mutant mice.
Cardiovasc Res. 2020; 116(2):339-352
Doi: 10.1093/cvr/cvz119
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- Co-authors Med Uni Graz
- Birner-Grünberger Ruth
- Eichmann Thomas
- Höfler Gerald
- Kolb Dagmar
- Krenn Petra Johanna
- Madl Tobias
- Schoiswohl Gabriele Maria
- Stryeck Sarah
- Tomin Tamara
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- Abstract:
- AIMS: Lipotoxic cardiomyopathy in diabetic and obese patients typically encompasses increased cardiac fatty acid (FA) uptake eventually surpassing the mitochondrial oxidative capacity. Lowering FA utilization via inhibition of lipolysis represents a strategy to counteract the development of lipotoxic heart dysfunction. However, defective cardiac triacylglycerol (TAG) catabolism and FA oxidation in humans (and mice) carrying mutated ATGL alleles provokes lipotoxic heart dysfunction questioning a therapeutic approach to decrease cardiac lipolysis. Interestingly, decreased lipolysis via cardiac overexpression of Perilipin 5 (Plin5), a binding partner of ATGL, is compatible with normal heart function and lifespan despite massive cardiac lipid accumulation. Herein, we decipher mechanisms that protect Plin5 transgenic mice from the development of heart dysfunction. METHODS AND RESULTS: We generated mice with cardiac-specific overexpression of Plin5 encoding a serine-155 to alanine exchange (Plin5-S155A) of the protein kinase A phosphorylation site, which has been suggested as a prerequisite to stimulate lipolysis and may play a crucial role in the preservation of heart function. Plin5-S155A mice showed a substantial increase in cardiac TAG and ceramide levels, which was comparable to mice overexpressing non-mutated Plin5. Lipid accumulation was compatible with normal heart function even under mild stress. Plin5-S155A mice showed reduced cardiac FA oxidation but normal ATP production and changes in the Plin5-S155A phosphoproteome compared to Plin5 transgenic mice. Interestingly, mitochondrial recruitment of dynamin-related protein 1 (Drp1) was markedly reduced in cardiac muscle of Plin5-S155A and Plin5 transgenic mice accompanied by decreased phosphorylation of mitochondrial fission factor, a mitochondrial receptor of Drp1. CONCLUSIONS: This study suggests that low cardiac lipolysis is associated with reduced mitochondrial fission and may represent a strategy to combat the development of lipotoxic heart dysfunction.
- Find related publications in this database (using NLM MeSH Indexing)
- Adenosine Triphosphate - metabolism
- Adipose Tissue - metabolism, pathology
- Animals - administration & dosage
- COS Cells - administration & dosage
- Ceramides - metabolism
- Chlorocebus aethiops - administration & dosage
- Disease Models, Animal - administration & dosage
- Dynamins - metabolism
- Fatty Acids - metabolism
- Heart Diseases - genetics, metabolism, physiopathology, prevention & control
- Intracellular Signaling Peptides and Proteins - genetics, metabolism
- Lipolysis - administration & dosage
- Membrane Proteins - metabolism
- Mice, Mutant Strains - administration & dosage
- Mitochondria, Heart - metabolism, pathology
- Mitochondrial Dynamics - administration & dosage
- Mitochondrial Proteins - metabolism
- Muscle Proteins - genetics, metabolism
- Mutation - administration & dosage
- Myocytes, Cardiac - metabolism, pathology
- Oxidation-Reduction - administration & dosage
- Phosphorylation - administration & dosage
- Rats - administration & dosage
- Signal Transduction - administration & dosage
- Triglycerides - metabolism
- Find related publications in this database (Keywords)
- Cardiac lipolysis
- Lipotoxicity
- Perilipin 5
- Mitochondrial dynamics
- Heart dysfunction