Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores

Abstract

Fatty acids (FAs) are essential components of all lipid classes and pivotal substrates for energy production in all vertebrates. Additionally, they act directly or indirectly as signaling molecules and, when bonded to amino acid side chains of peptides, anchor proteins in biological membranes. In vertebrates, FAs are predominantly stored in the form of triacylglycerol (TG) within lipid droplets of white adipose tissue. Lipid droplet-associated TGs are also found in most nonadipose tissues, including liver, cardiac muscle, and skeletal muscle. The mobilization of FAs from all fat depots depends on the activity of TG hydrolases. Currently, three enzymes are known to hydrolyze TG, the well-studied hormone-sensitive lipase (HSL) and monoglyceride lipase (MGL), discovered more than 40 years ago, as well as the relatively recently identified adipose triglyceride lipase (ATGL). The phenotype of HSL-and ATGL-deficient mice, as well as the disease pattern of patients with defective ATGL activity (due to mutation in ATGL or in the enzymeʼs activator, CGI-58), suggest that the consecutive action of ATGL, HSL, and MGL is responsible for the complete hydrolysis of a TG molecule. The complex regulation of these enzymes by numerous, partially uncharacterized effectors creates the "lipolysome," a complex metabolic network that contributes to the control of lipid and energy homeostasis. This review focuses on the structure, function, and regulation of lipolytic enzymes with a special emphasis on ATGL.-Zechner, R., P. C. Kienesberger, G. Haemmerle, R. Zimmermann, and A. Lass. Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores. J. Lipid Res. 2009. 50: 3-21.Supplementary key words lipolysis • hydrolase • neutral lipid storage disease Lipid homeostasis reflects a balance of processes, designed to generate fatty acids (FAs) and lipids, deliver them from their site of origin to target tissues, and catabolize them for metabolic purposes. Innumerable genes and signal components are responsible for an integrated communication network between many tissues and organs, including adipose tissue, liver, muscles, the digestive tract, pancreas, and the nervous system. This network ultimately accounts for the accurate regulation of lipid and energy homeostasis. Despite the central physiological importance of these processes for human health, many basic mechanisms regulating the synthesis, uptake, storage, and utilization of lipids remain insufficiently characterized.FAs are vital components of essentially all known organisms. They are important substrates for oxidation and the production of cellular energy. FAs are essential precursors for all lipid classes, including those forming biological membranes. Finally, they are important for protein function in acylated proteins and as ligands for nuclear receptor transcription factors. In contrast to these "beneficial" characteristics, unesterified FAs can become deleterious for cells when present even at relatively low concentrations. The chronic exposure of nona...

Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA

“…ATGL has recently been demonstrated to be the first and rate-limiting step in triacylglycerol hydrolysis. The sequential actions of ATGL, hormone-sensitive lipase, and monoglyceride lipase result in release of energy from stored lipid droplets as fatty acid and glycerol (43). In addition to its role in adipocyte hormone-sensitive triacylglycerol hydrolysis, ATGL has also been demonstrated to function in basal lipolysis (31).…”

Ontogenesis of muscle and adipose tissues and their interactions in ruminants and other species

“…However, this concept was challenged recently by (i) studies on hormone-sensitive lipase-null mice maintaining a residual fat cell lipolysis, (ii) the identification of a novel adipocyte TAG lipase named adipose triglyceride lipase (ATGL), desnutrin or phospho-lipase A2 (Lafontan and Langin, 2009). The current understanding of the lipolysis steps is that at least three major lipases cooperate to release three FA molecules and one glycerol molecule from each TAG molecule (Lafontan and Langin, 2009;Zechner et al, 2009). Similarly in BAT, lipases promote the hydrolysis of stored TAG, leading to the mobilization of FAs as fuel for thermogenesis.…”

“…Similarly in BAT, lipases promote the hydrolysis of stored TAG, leading to the mobilization of FAs as fuel for thermogenesis. The high ATGL activity in BAT together with the impaired thermogenesis in ATGL-null mice, while HSL-null mice exhibited normal thermogenesis, suggest that ATGL is essential for the provision of FA as substrate for BAT thermogenesis (Zechner et al, 2009). To date, only HSL has been identified in bovine WAT through its mRNA abundance (Bonnet et al, 1998;Sumner and Mcnamara, 2007;Xu et al, 2008) and its activity (Sprinkle et al, 1998;Kazala et al, 2003).…”

Adipose tissue metabolism and inflammation are differently affected by weight loss in obese mice due to either a high-fat diet restriction or change to a low-fat diet

“…Its expression is regulated by nutritional status and is associated with rates of adipose tissue lipolysis. In contrast, levels of hormone-sensitive lipase (Hsl/Lipe) are not regulated by nutritional status and are decreased in acute fasting and increase after prolonged restriction (Zechner et al 2009). Here, we show that levels of lipolysis are not affected by the restriction, although there seems to be a tendency for increased levels in the HFD-CR mice as compared to the LFD mice (Fig.…”