Adipose Triglyceride Lipase and Hormone-sensitive Lipase Are the Major Enzymes in Adipose Tissue Triacylglycerol Catabolism

TLDR

Free fatty acid mobilization from adipose triacylglycerol stores depends on triacylglycerol lipases. The study aims to demonstrate that adipose triglyceride lipase (ATGL) and hormone‑sensitive lipase (HSL) are the principal enzymes driving TG breakdown in murine white adipose tissue. The authors used ATGL‑ or HSL‑deficient mice and a selective HSL inhibitor to dissect the specific contributions of each enzyme to adipose TG catabolism. The selective HSL inhibitor 76‑0079 had no effect on TG catabolism in HSL‑deficient WAT but nearly abolished free fatty acid release in ATGL‑deficient fat, CGI‑58 stimulated ATGL but not HSL activity, and ATGL and HSL together account for over 95 % of TG hydrolase activity in murine WAT, with other lipases contributing only minimally.

Abstract

The mobilization of free fatty acids from adipose triacylglycerol (TG) stores requires the activities of triacylglycerol lipases. In this study, we demonstrate that adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major enzymes contributing to TG breakdown in in vitro assays and in organ cultures of murine white adipose tissue (WAT). To differentiate between ATGL- and HSL-specific activities in cytosolic preparations of WAT and to determine the relative contribution of these TG hydrolases to the lipolytic catabolism of fat, mutant mouse models lacking ATGL or HSL and a mono-specific, small molecule inhibitor for HSL (76-0079) were used. We show that 76-0079 had no effect on TG catabolism in HSL-deficient WAT but, in contrast, essentially abolished free fatty acid mobilization in ATGL-deficient fat. CGI-58, a recently identified coactivator of ATGL, stimulates TG hydrolase activity in wild-type and HSL-deficient WAT but not in ATGL-deficient WAT, suggesting that ATGL is the sole target for CGI-58-mediated activation of adipose lipolysis. Together, ATGL and HSL are responsible for more than 95% of the TG hydrolase activity present in murine WAT. Additional known or unknown lipases appear to play only a quantitatively minor role in fat cell lipolysis.