Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewFate of fat: The role of adipose triglyceride lipase in lipolysis
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.
Section snippets
Lipid droplets: dynamic cellular organelles
The principal substrate for lipolytic enzymes, cellular TG, are stored in cytosolic LDs in essentially all tissues of the body. LDs exhibit a particle core composed of TG and cholesteryl esters and are surrounded by a phospholipid monolayer that contains numerous proteins with structural, regulatory or enzymatic functions [5], [6]. LD cage proteins are characterized by the presence of PAT domains in their primary sequence. The PAT domain is defined by a conserved amino acid sequence present in p
HSL
The classical and for many decades considered the only enzyme responsible for the hydrolysis of TG is HSL. Originally described in the early 60's [21], [22], HSL was shown to exhibit broad substrate specificity capable of hydrolyzing cholesterylester, tri-, di-, and monoacylglycerol (TG, DG and MG), retinyl ester, and numerous water soluble ester substrates [23], [24]. The enzyme is most active against DG which is hydrolyzed ∼ 10 fold faster than TG. For decades, it was assumed that HSL is the
ATGL
In 2004, three groups independently reported an enzyme capable of hydrolyzing TG. The TG hydrolase was named adipose triglyceride lipase (ATGL) [35], desnutrin [36], or phospholipase A2ξ [37]. ATGL is highly expressed in adipose tissue and its expression markedly increases during 3T3-L1 adipocyte differentiation [35], [36], [38], [39]. ATGL expression is also observed in cardiac muscle [40], type I fibers of skeletal muscle [41], testis, macrophages (unpublished observation), liver [42], and
ATGL deficiency in mice
The important role of ATGL in lipolysis became evident when parameters of lipid and energy metabolism were analyzed in ATGL-deficient (ATGL-ko) mice [40]. In contrast to HSL-deficient mice exhibiting decreased fat mass, ATGL-ko animals had enlarged fat depots and the TG hydrolase activities in WAT lysates were drastically reduced (∼ 80%). ATGL-deficiency decreased the release of FA from WAT by ∼ 70% in response to isoproterenol treatment and this decreased lipolytic rate resulted in substantially
ATGL deficiency in humans
Recently, mutations in the human ATGL gene were described that are associated with functional defects of the enzyme and the accumulation of lipids in multiple tissues [45], [46], [47]. Currently, only five individuals affected with this autosomal recessive disorder have been described. According to Fischer et al. [45], the human condition of ATGL deficiency is named Neutral Lipid Storage Disease with myopathy (NLSDM). In addition to the systemic TG accumulation, patients invariably suffer from
ATGL regulation: ATGL activity is “hormone-sensitive”
Experiments in HSL-deficient adipose tissue showed that the remnant lipolytic activity can be activated by β-adrenergic stimulation [28], [52]. Already before the discovery of ATGL, this observation suggested that the non-HSL activity is “hormone-sensitive”. With the discovery of ATGL and the availability of ATGL-ko mice it became evident that ATGL activity is stimulated by isoproterenol and inhibited by insulin. The mechanisms how hormones affect ATGL enzyme action require better
ATGL regulation: CGI-58
In 2006, Lass et al. [60] showed that ATGL activity is strongly stimulated by an activator protein annotated as α/β hydrolase domain containing protein 5 [ABHD5; also known as comparative gene identification-58 (CGI-58)]. Mouse ATGL is up to 20-fold more active in the presence of CGI-58. Human CGI-58 also activates human ATGL although the magnitude of activation is less pronounced (∼ 5-fold). The finding that ATGL requires a coactivator is not unexpected because several other TG hydrolases that
Molecular mechanisms regulating lipolysis
Studies in perilipin-deficient mice [64], [65] and in vitro experiments [7], [8], [9] indicated a dual role for perilipin in lipolysis: Under basal, non-hormone stimulated conditions, perilipin protects the LD from lipolysis, whereas in stimulated cells phosphorylated perilipin facilitates lipid degradation. The molecular basis of HSL activation is its translocation from the cytosol to the lipid droplet in response to hormonal stimulation and perilipin is essential for the translocation
Regulation of ATGL in non-adipose tissues
Although the reversible interaction of CGI-58 with perilipin represents a potential regulatory event in adipocytes, many aspects of ATGL regulation remain unclear. First, this mechanism is restricted to perilipin expressing cells and tissues such as adipose tissue and adrenals. However, it is well established that ATGL and CGI-58 also play an important role in other tissues such as muscle and liver, which do not express perilipin. Thus, additional mechanisms must exist that regulate ATGL
Conclusion
Data from ATGL-deficient mice and humans with mutations in PNPLA2, the gene coding for ATGL assign a central role to this enzyme for the catabolism of cellular fat stores.
Do we now understand lipolysis? No. Despite the discovery of ATGL and its activator as well as the elucidation of the role of certain PAT proteins in lipolysis, numerous issues remain unsettled. I) The regulation and function of ATGL and CGI-58 are incompletely understood. Currently it is unknown how phosphorylation affects
Acknowledgements
This research was supported by the grants SFB LIPOTOX F30 and P18434-B05 which are funded by the Austrian Fonds zur Förderung der wissenschaftlichen Forschung (FWF) and ''GOLD – Genomics of Lipid-Associated Disorders'', which is part of the Austrian Genome Project ''GEN-AU Genome research in Austria'' funded by the Austrian Ministry for Science and Research (BMWF) and the Austrian Forschungsförderungsgesellschaft FFG.
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