title: The interplay of protein kinase A and perilipin 5 regulates cardiac lipolysis.
abstract: Defective lipolysis in mice lacking adipose triglyceride lipase provokes severe cardiac steatosis and heart dysfunction, markedly shortening life span. Similarly, cardiac muscle (CM)-specific Plin5 overexpression (CM-Plin5) leads to severe triglyceride (TG) accumulation in cardiomyocytes via impairing TG breakdown. Interestingly, cardiac steatosis due to overexpression of Plin5 is compatible with normal heart function and life span indicating a more moderate impact of Plin5 overexpression on cardiac lipolysis and energy metabolism. We hypothesized that cardiac Plin5 overexpression does not constantly impair cardiac lipolysis. In line with this assumption, TG levels decreased in CM of fasted compared with nonfasted CM-Plin5 mice indicating that fasting may lead to a diminished barrier function of Plin5. Recent studies demonstrated that Plin5 is phosphorylated, and activation of adenylyl cyclase leads to phosphorylation of Plin5, suggesting that Plin5 is a substrate for PKA. Furthermore, any significance of Plin5 phosphorylation by PKA in the regulation of TG mobilization from lipid droplets (LDs) is unknown. Here, we show that the lipolytic barrier of Plin5-enriched LDs, either prepared from cardiac tissue of CM-Plin5 mice or Plin5-transfected cells, is abrogated by incubation with PKA. Notably, PKA-induced lipolysis of LDs enriched with Plin5 carrying a single mutation at serine 155 (PlinS155A) of the putative PKA phosphorylation site was substantially impaired revealing a critical role for PKA in Plin5-regulated lipolysis. The strong increase in protein levels of phosphorylated PKA in CM of Plin5 transgenic mice may partially restore fatty acid release from Plin5-enriched LDs, rendering these hearts compatible with normal heart function despite massive steatosis.
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Nina M
authors.initials: NM
authors.lastname: Pollak
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Jaeger
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kolleritsch
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria guenter.haemmerle@uni-graz.at.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D005951:Glucose Tolerance Test; D006321:Heart / Q000502:physiology*; D006331:Heart Diseases / Q000378:metabolism; D007328:Insulin / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D050356:Lipid Metabolism; D008055:Lipids / Q000737:chemistry; D008066:Lipolysis / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation; D014162:Transfection
chemical_list: D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D009124:Muscle Proteins; C551268:lipid storage droplet protein 5, mouse; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Adipose Triglyceride Lipase (ATGL); Cardiac Metabolism; Cardiac Muscle; Comparative Gene Identification-58; Lipase; Lipid Droplet; Lipolysis; Perilipin 5; Protein Kinase A (PKA); Triacylglycerol