Fate of fat: The role of adipose triglyceride lipase in lipolysis

Abstract

Lipolysis, the coordinated catabolism of triacylglycerol (TG) stored in cellular lipid droplets, provides fatty acids, di-, and monoglycerides. These products are important energy substrates, precursors for other lipids, or lipid signaling molecules. Following their discovery by Hollenberg, C.H., Raben, M.S., and Astwood, E.B.(1961) and Vaughan, M., Berger, J.E., and Steinberg, D. (1964), hormone-sensitive lipase (HSL) and monoacylglycerol lipase stayed in the focus of research for three decades. Within the last decade, however, it became evident that the lipolytic pathway is incompletely understood. Studies on the regulation of lipolysis and the characterization of HSL-deficient mice indicated that additional previously unrecognized factors that contribute to fat catabolism must exist. This led to the discovery of the perilipin, adipophilin, Tip47 (PAT) family of lipid droplet binding proteins and the identification of a novel TG hydrolase named adipose triglyceride lipase (ATGL). This review focuses on the importance of ATGL as TG lipase within the “lipolytic machinery” and the current knowledge of molecular mechanisms that regulate ATGL activity.

Introduction

Unesterified fatty acids (FA) are biomolecules that serve multiple functions. FA represent constituents of essentially all lipid classes, regulate gene expression by acting directly or indirectly as ligands for nuclear receptors, affect protein function by post-transcriptional acylation of target peptides, and, above all, serve as the most energy-dense substrate in the body for the production of ATP. However, excessive cellular concentrations of FA are toxic to cells and tissues. Because of their amphipathic nature, FA act as detergents, damage cell and organelle membranes, and perturb the cellular acid/base homeostasis. To avoid toxicity, FA are esterified with glycerol and the resulting triacylglycerols (TG) are deposited in lipid droplets (LDs) in essentially all cells of the body. Accordingly, TG stores function as buffer for incoming lipids to prevent lipotoxic free fatty acid (FFA) concentrations [1], [2]. White adipose tissue (WAT) represents by far the most efficient organ to store excessive amounts of circulating FA during the postprandial period. At times of demand, FA are released from cellular LDs by the action of TG hydrolases, a process called lipolysis. Initially, the limited amount of lipids present in most tissues is hydrolyzed. During prolonged fasting, however, these stores are not sufficient to meet the requirements of FA for energy production and fat stores must be mobilized by the induction of lipolysis in adipocytes.

Only a carefully regulated balance of lipid synthesis and lipolysis in WAT and other tissues will maintain whole body energy homeostasis. Dysregulation of these processes may be linked to metabolic disorders like obesity, lipodystrophy, type 2 diabetes, and the metabolic syndrome [3]. Current evidence suggests that TG are hydrolyzed in a sequential process involving different lipases. ATGL and HSL are necessary for proper hydrolysis of tri- and diglycerides, respectively. The last step in lipolysis is performed by monoglyceride lipase (MGL), which hydrolyzes monoglycerides to form glycerol and fatty acids. The activity of ATGL and HSL is tightly regulated by hormones. In contrast, to our knowledge no evidence exists that MGL activity is affected by hormonal stimulation. However, in vitro experiments suggest that the enzyme is required for complete degradation of TG [4]. This review will summarize the current knowledge of function and regulation of ATGL and HSL in adipose and non-adipose tissues with a special emphasis on ATGL.