Studies on the substrate and stereo/regioselectivity of adipose triglyceride lipase, hormone-sensitive lipase, and diacylglycerol-O-acyltransferases.
Adipose triglyceride lipase (ATGL) is rate-limiting for the initial step of triacylglycerol (TAG) hydrolysis, generating diacylglycerol (DAG) and fatty acids. DAG exists in three stereochemical isoforms. Here we show that ATGL exhibits a strong preference for the hydrolysis of long-chain fatty acid esters at the sn-2 position of the glycerol backbone. The selectivity of ATGL broadens to the sn-1 position upon stimulation of the enzyme by its co-activator CGI-58. sn-1,3 DAG is the preferred substrate for the consecutive hydrolysis by hormone-sensitive lipase. Interestingly, diacylglycerol-O-acyltransferase 2, present at the endoplasmic reticulum and on lipid droplets, preferentially esterifies sn-1,3 DAG. This suggests that ATGL and diacylglycerol-O-acyltransferase 2 act coordinately in the hydrolysis/re-esterification cycle of TAGs on lipid droplets. Because ATGL preferentially generates sn-1,3 and sn-2,3, it suggests that TAG-derived DAG cannot directly enter phospholipid synthesis or activate protein kinase C without prior isomerization.
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Thomas O
TO
Eichmann
Manju
M
Kumari
Joel T
JT
Haas
Robert V
RV
Farese
Robert
R
Zimmermann
Achim
A
Lass
Rudolf
R
Zechner
D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003001:Cloning, Molecular; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D008049:Lipase / Q000378:metabolism*; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D013237:Stereoisomerism; D002787:Sterol Esterase / Q000378:metabolism*; D010738:Type C Phospholipases / Q000737:chemistry
D020033:Protein Isoforms; D051048:Diacylglycerol O-Acyltransferase; D005982:Glutathione Transferase; D011493:Protein Kinase C; D002787:Sterol Esterase; D008049:Lipase; D010738:Type C Phospholipases