Adipose triglyceride lipase activity is inhibited by long-chain acyl-coenzyme A.
Adipose triglyceride lipase (ATGL) is required for efficient mobilization of triglyceride (TG) stores in adipose tissue and non-adipose tissues. Therefore, ATGL strongly determines the availability of fatty acids for metabolic reactions. ATGL activity is regulated by a complex network of lipolytic and anti-lipolytic hormones. These signals control enzyme expression and the interaction of ATGL with the regulatory proteins CGI-58 and G0S2. Up to date, it was unknown whether ATGL activity is also controlled by lipid intermediates generated during lipolysis. Here we show that ATGL activity is inhibited by long-chain acyl-CoAs in a non-competitive manner, similar as previously shown for hormone-sensitive lipase (HSL), the rate-limiting enzyme for diglyceride breakdown in adipose tissue. ATGL activity is only marginally inhibited by medium-chain acyl-CoAs, diglycerides, monoglycerides, and free fatty acids. Immunoprecipitation assays revealed that acyl-CoAs do not disrupt the protein-protein interaction of ATGL and its co-activator CGI-58. Furthermore, inhibition of ATGL is independent of the presence of CGI-58 and occurs directly at the N-terminal patatin-like phospholipase domain of the enzyme. In conclusion, our results suggest that inhibition of the major lipolytic enzymes ATGL and HSL by long-chain acyl-CoAs could represent an effective feedback mechanism controlling lipolysis and protecting cells from lipotoxic concentrations of fatty acids and fatty acid-derived lipid metabolites.
Institute of Molecular Biosciences, University of Graz, Austria.
Harald M
HM
Nagy
Institute of Molecular Biosciences, University of Graz, Austria.
Margret
M
Paar
Institute of Molecular Biosciences, University of Graz, Austria.
Christoph
C
Heier
Institute of Molecular Biosciences, University of Graz, Austria.
Tarek
T
Moustafa
Institute of Molecular Biosciences, University of Graz, Austria.
Peter
P
Hofer
Institute of Molecular Biosciences, University of Graz, Austria.
Guenter
G
Haemmerle
Institute of Molecular Biosciences, University of Graz, Austria.
Achim
A
Lass
Institute of Molecular Biosciences, University of Graz, Austria.
Rudolf
R
Zechner
Institute of Molecular Biosciences, University of Graz, Austria.
Monika
M
Oberer
Institute of Molecular Biosciences, University of Graz, Austria. Electronic address: robert.zimmermann@uni-graz.at.
Robert
R
Zimmermann
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000201:enzymology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008066:Lipolysis / Q000235:genetics*; D002787:Sterol Esterase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D000214:Acyl Coenzyme A; D018797:Cell Cycle Proteins; D005227:Fatty Acids; C508073:G0S2 protein, human; D014280:Triglycerides; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human; D002787:Sterol Esterase; D008049:Lipase
Adipose triglyceride lipase; Hormone-sensitive lipase; Lipolysis; Regulation; acyl-CoA