Adipose Triglyceride Lipase

Abstract

Adipose triglyceride lipase (ATGL) is a recently described adipose-enriched protein with triglyceride-specific lipase activity. ATGL shares the greatest sequence homology with adiponutrin, a nutritionally regulated protein of unclear biological function. Here we present a functional analysis of ATGL and adiponutrin and describe their regulation by insulin. Retroviral-mediated overexpression of ATGL in 3T3-L1 adipocytes increased basal and isoproterenol-stimulated glycerol and nonesterified fatty acid (NEFA) release, whereas siRNA-mediated knockdown of ATGL had the opposite effect. In contrast, siRNA-mediated knockdown of adiponutrin in 3T3-L1 adipocytes had no effect on glycerol or NEFA release. In mice, both ATGL and adiponutrin are nutritionally regulated in adipose tissue, with ATGL being upregulated and adiponutrin being downregulated by fasting. In 3T3-L1 adipocytes, insulin decreased ATGL and increased adiponutrin expression in a dose-and time-dependent manner, suggesting that insulin directly mediates this nutritional regulation. In addition, adipose expression of ATGL was increased by insulin deficiency and decreased by insulin replacement in streptozotocininduced diabetic mice and was increased in fat-specific insulin receptor knockout mice, whereas adiponutrin showed the opposite pattern. These data suggest that murine ATGL but not adiponutrin contributes to net adipocyte lipolysis and that ATGL and adiponutrin are oppositely regulated by insulin both in vitro and in vivo. Diabetes 55: 148 -157, 2006 A dipose tissue triglycerides are the predominant form of energy storage in animals. The ability to store and release this energy in response to variable energy availability is advantageous to survival and requires a carefully regulated balance between triglyceride synthesis and hydrolysis. Dysregulation of these processes may result in metabolic disorders, such as obesity and lipodystrophy, which are associated with dyslipidemia, insulin resistance, and overt diabetes. Hence understanding the regulatory mechanisms underlying the storage and mobilization of triglycerides is essential to understanding the pathophysiology of obesity, diabetes, and related metabolic disorders.Hormone-sensitive lipase (HSL) has traditionally been considered the key lipolytic enzyme in adipocytes (1-4). Lipolytic hormones such as catecholamines stimulate lipolysis primarily via cAMP-mediated activation of protein kinase (PK) A. PKA then phosphorylates HSL and perilipin A. Phosphorylation of perilipin A alleviates the barrier function of this protein and prompts its active participation in the lipolytic process. Phosphorylation of HSL results in translocation of HSL from the cytosol to the lipid droplet where it catalyzes the hydrolysis of tri-, di-, and monoglycerides; cholesteryl esters; and other substrates. Insulin acutely inhibits lipolysis, at least in part, via inhibition of the above cAMP-dependent pathway by PKBdependent phosphorylation and activation of phosphodiesterase 3B, which in turn lowers cAMP levels (5). How...

PPARγ agonism increases rat adipose tissue lipolysis, expression of glyceride lipases, and the response of lipolysis to hormonal control

“…Three independent groups have discovered a protein-alternatively termed adipose triglyceride lipase (ATGL) [12], desnutrin [13] or calcium-independent phospholipase A 2 /lipase ζ (iPLA 2 ζ) [14]-that fulfils all the predicted characteristics of this new lipase: a preference for the hydrolysis of the first triglyceride ester bond, drastically reduced lipolysis following antibody or antisense ATGL inhibition, and enhanced basal and isoproterenol-stimulated lipolysis following ATGL overexpression [15]. ATGL therefore plays a particularly important role in the control of basal lipolysis, but also appears to participate in the lipolytic response to adrenergic stimulation [16].…”

“…A fairly robust correlation was found between basal rates of release of lipolytic products and mRNA levels of ATGL. This correlation obviously does not establish a cause and effect relationship; however, the importance of the expression level of ATGL in WAT lipolysis is highlighted by recent studies in which ATGL overexpression in 3T3-L1 adipocytes enhanced both fasting basal and isoproterenolstimulated lipolysis, whereas the opposite effects were found with inhibition of ATGL through antisense technology [12,16,27]. The functional importance of lipase .…”

PNPLA3 gene in liver diseases

“…(SREBP-1c) and carbohydrate response element binding protein (ChREBP) [74][75][76]. In human stellate cells, PNPLA3 is also downregulated by intracellular retinol levels [72].…”

Islet beta cell failure in the 60% pancreatectomised obese hyperlipidaemic Zucker fatty rat: severe dysfunction with altered glycerolipid metabolism without steatosis or a falling beta cell mass

“…Results are expressed as fold change over corresponding Sham animals and have been normalised to cyclophilin A. Means±SEM of four to eleven rats. *p<0.05, **p<0.01, ***p<0.001 compared with Sham rats (unpaired two-tailed Student's t test) low-activity lipase enzyme that is implicated in energy balance [31]); (3) a 22% decrease in Pdx1 (a key islet beta cell differentiation factor); (4) 35% and 45% decreases in the incretin receptors of GLP-1 (Glp1r) and GIP (Gipr) respectively; (5) a 37% decrease in Ffar1 (also known as Gpr40; encodes a receptor for NEFA); (6) a 34% decrease in the key beta cell anaplerosis gene Pc (a similar decrease was observed at the protein level of pyruvate carboxylase; not shown); and (7) a 34% decrease in the Ins2 (insulin) gene (Fig. 7).…”