review Lipolysis and lipases in white adipose tissue – An update Andressa Bolsoni-Lopes1, Maria Isabel C. Alonso-Vale2 1 Departamento de Fisiologia e ABSTRACT Biofísica, Instituto de Ciências Lipolysis is defined as the sequential hydrolysis of triacylglycerol (TAG) stored in cell lipid droplets. Biomédicas, Universidade de São For many years, it was believed that hormone-sensitive lipase (HSL) and monoacylglycerol lipase Paulo (USP), São Paulo, SP, Brazil 2 (MGL) ​​were the main enzymes catalyzing lipolysis in the white adipose tissue. Since the discovery Departamento de Ciências Biológicas, Instituto de Ciências of adipose triglyceride lipase (ATGL) in 2004, many studies were performed to investigate and char- Ambientais, Químicas e acterize the actions of this lipase, as well as of other proteins and possible regulatory mechanisms Farmacêuticas, Universidade involved, which reformulated the concept of lipolysis. Novel findings from these studies include the Federal de São Paulo (Unifesp), identification of lipolytic products as signaling molecules regulating important metabolic processes Diadema, SP, Brazil in many non-adipose tissues, unveiling a previously underestimated aspect of lipolysis. Thus, we Correspondence to: present here an updated review of concepts and regulation of white adipocyte lipolysis with a special Maria Isabel C. Alonso Vale emphasis in its role in metabolism homeostasis and as a source of important signaling molecules. Departamento de Ciências Biológicas, Arch Endocrinol Metab. 2015;59(4):335-42 Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Keywords Universidade Federal de São Paulo Av. São Nicolau, 210 Adipose triglyceride lipase; hormone-sensitive lipase; monoacylglycerol lipase; perilipin; triacylglycerol hydrolysis 09913-030 – Diadema, SP, Brazil [email protected] Received on Mar/9/2015 Accepted on Apr/22/2015 DOI: 10.1590/2359-3997000000067 INTRODUCTION and delimit the lipid droplet, or make lipid hydrolysis re-formed lipids that come from the diet or even easier (7,8). P those that are synthetized are stored mainly in the The amount of TAG stored in the adipocytes, which white adipose tissue (WAT) as triacylglycerols (TAG), are in a constant flow in the TAG-fatty acid cycle, de- neutral lipids made up of three fatty acids esterified pends on the balance between lipogenesis (the biosyn- to the carbon backbone of a glycerol molecule (1-3). thesis, incorporation, and storage of TAG in the lipid The WAT, described as the main energy reservoir in droplet in the cytoplasm), and lipolysis (the sequential mammals, has a mesenchymal origin and is made up hydrolysis of TAG, fatty acids, and glycerol) (1,9,10). by a matrix of connective tissue, immune system cells, In prolonged periods of positive energy balance, which bloods vessels, sympathetic innervation, stem cells and result from excessive consumption of high-calorie pre-adipocytes, as well as adipocytes, cells specialized in foods added to the lack of physical activity, adiposity the intake, storage, and mobilization of fat (4). increases. This chronic process may lead to the devel- Adipocytes store TAG in a single, large lipid drop- opment of obesity (11,12). On the other hand, in pro- let that takes up 85-90% of the cytoplasm and pushes longed periods of fasting or of high demands of energy, the nucleus and a fine cytosol layer to the periphery of lipolysis is essential to supply fatty acids and glycerol as the cell. The lipid droplet is recognized as a dynamic energy substrates to tissues. However, changes in this cell organelle, surrounded by a monolayer of phospho- process have frequently been associated with lipodys- lipids, structural proteins, and enzymes, which pro- trophy, hyperlipidemia, insulin resistance, and obesity tects cell organelles from the cytotoxic effects of fatty (12,13). acids (5-7). Among the several proteins that make up For many years, it was believed that hormone-sen- this monolayer, perilipin 1A may be emphasized, as it sitive lipase (HSL) and monoacyglycerol lipase (MGL) AE&M all rights reserved. is the main perilipin found in the adipocyte. Depend- were the main enzymes involved in WAT lipolysis. © ing on its activation status, perilipin 1A may protect However, after the discovery of the adipose triglyceride Copyright Arch Endocrinol Metab. 2015;59/4 335 Lipolysis in white adipose tissue lipase (ATGL) in 2004 (14-16) and the later character- In relation to glycerol produced in the lipolytic pro- ization of its actions and regulation mechanism, a new cess, most of it is released into the bloodstream and concept of lipolysis was proposed. During this period, mainly functions as substrates for glucose production in evidence was found that indicated that, besides provid- liver gluconeogenesis (3). Recently, with the discovery ing energy, final and intermediate products generated of the presence glycerol kinase, an enzyme the converts in the lipolysis process may act as signaling molecules glycerol into glycerol 3-phosphate, and its activity in that regulate important metabolic process in many adipocytes raised the hypothesis that part of the glyc- non-adipose tissues, unveiling previously underestima- erol produced by lipolysis may be recycled into TAG ted aspects of lipolysis. Therefore, we present here an still inside of this cell (18). updated review of lipolysis concepts and regulation in Lipolysis is a process that occurs under non-stim- white adipocytes, with special emphasis in its role as a ulated (basal conditions) or in conditions stimulated source of important signaling molecules in the control by hormones (19,20). In basal conditions, HSL pre- of metabolic homeostasis. dominantly remains in the cytosol, whereas perilipin, ATGL and its co-activator, protein Abhd5 (abhydrolase domain-containing 5), also called CGI-58 (compara- LIPOLYSIS IN WHITE ADIPOCYTES tive gene identification 58), are found on the surface Lipolysis consists of the sequential hydrolysis of TAG of the lipid droplet (7). ATGL is highly specific for to its constituent molecules glycerol and three fatty ac- TAG hydrolysis, and it is responsible for large part of ids, catalyzed by three different enzymes. In the first the lipolytic activity found both in basal and stimulated stage of this process, TAG is hydrolyzed to diacylglyc- conditions. However, in basal conditions, the co-acti- erol (DAG) and one molecule of fatty acid, in a reac- vator CGI-58 remains bound to perilipin (forming an tion mainly catalyzed by the enzyme ATGL. After that, inactive complex), that limits the hydrolytic activity of DAG is converted to monoacylglycerol (MAG) and a lipase (9,19). second fatty acid by the action of HSL. In the end, In periods of fasting or high energy demands, the MGL hydrolyses MAG, producing glycerol and a last adipocyte is stimulate by hormones, mainly by the fatty acid (9,13) (Figure 1). action of catecholamines, leading to a series of intra- cellular reactions that culminates in the activation of protein kinase A and G (PKA/PKG), which promotes the phosphorylation of HSL and perilipin (19,21,22). After phosphorylation, HSL is translocated into the lipid droplet and acts together with ATGL, accelerating Figure 1. Sequential hydrolysis of triacylglycerol. the lipolytic process. Together, ATGL and HSL are re- FA: fatty acid; ATGL: adipose triglyceride lipase; DAG: diacylglycerol; HSL: sponsible for about 95% of the hydrolysis of TAG (23). hormone-sensitive lipase; MGL: monoacylglycerol lipase; MAG: Similarly, after the phosphorylation of perilipin, the po- monoacylglycerol; TAG: triacylglycerol. sition of this compound on the lipid droplet changes, making TAG hydrolysis by the lipases easier. With the Fatty acids derived from lipolysis are, most of the phosphorylation of perilipin, CGI-58 is released and times, released in the bloodstream and bound to albu- binds to ATGL, forming an active complex and steeply min to be used as energy substrates by other tissues. increasing the action of this lipase (13,19,22). However, part of these molecules is kept inside adipo- HSL is more specific for DAG hydrolysis, and may cytes, acting as intracellular signaling mediators and also hydrolyze TAG and MAG, with lower efficiency, working as substrates for the synthesis of other fatty though. MGL, on the other hand, is located both in acids and lipids (including membrane lipids and other the cytosol of the cell and on the surface of the lip- lipids involved in cell metabolism), as gene transcrip- id droplet, and shows specificity for MAG hydrolysis, tion regulators, oxidation substrates or undergoing catalyzing the final step of lipolysis, that is, the conver- reesterification to make up TAG again. Approximately sion of MAG into glycerol and a free fatty acid (13,19) 30-40% of these fatty acids undergo this reesterifica- (Figure 2). AE&M all rights reserved. © tion, a process that is dependent on the intracellular ATGL shows strong specificity and/or selectivity Copyright generation of glycerol 3-phosphate (17). for the hydrolysis of the long-chain fatty acid esters (16 336 Arch Endocrinol Metab. 2015;59/4 Lipolysis in white adipose tissue or 18 carbons) found in position sn2 of the glycerol which has a molecular weight of 54 kDa, is found pre- backbone, which mainly includes the hydrolysis of pal- dominantly in white or brown adipose tissue, but is also mitoleic acid followed by palmitic and stearic acid. The seen in the testicles, pancreatic islets, cardiac muscle, main product of this reaction is 1,3-DAG, the prefer- and skeletal muscle (9). ATGL is nowadays considered ential substrate of the lipogenic enzyme diacylglycerol the main enzyme responsible for TAG hydrolysis, and acyltransferase 2 (DGAT2). This suggests that the en- is mainly located in the lipid droplet of adipocytes (1,7- zymes ATGL and DGAT act in a coordinated fashion 9,13). Therefore, its hydrolytic activity on TAG takes during the TAG hydrolysis/reesterification cycle. On place independent of the protein barrier that involves the other hand, after binding to CGI-58, ATGL starts the lipid droplet, making this lipase very important to hydrolyze fatty acids also found in position sn1, re- in basal lipolysis.