The Regulation of Adipose Triglyceride Lipase

The white adipose tissue serves as major storage site for triglycerides in mammals. Under fasting conditions or periods of high energy demand TG-derived free fatty acids (FFA) are released into the circulation and used for energy production. The mobilisation of FFA depends on the activity of lipolytic enzyms. During the last 20 years, hormone-sensitive lipase (HSL) has been considered as the rate-limiting enzyme in TG mobilization. However, from studies in HSL-deficient mice it is apparent that other enzymes must contribute to the mobilisation of triglyceride stores since HSL-deficient mice had normal body weight and were not obese. Futhermore, the HSL- deficient adipose tissue retained a basal and isoproternenol-stimulated lipolytic capacity. Recently, we discovered a novel triglyceride lipase which is predominantly expressed in adipose tissue. The enzyme was named "adipose triglyceride lipase" (ATGL) and specifically catalyzes first committed step in triglyceride hydrolysis resulting in the generation of diglycerides and FFA. The mobilisation of the triglyceride store is under tight hormonal control. Extensive studies have been performed to elucidate the hormonal signals and molecular mechanisms that activate HSL. So far, however, very little is known about the regulation of ATGL. The aim of current proposal is to identify the major regulatory mechanisms which control ATGL activity in adipose tissue and other organs. Identification of the mechanisms controlling ATGL action will substantially increase our knowledge about the lipolytic machinery in adipocytes and the regulation of FFA metabolism in mammals. Furthermore, ATGL might provide a novel therapeutic target for lipid-associated disorders.

The mobilization of free fatty acids (FFA) from white adipose tissue (WAT), a process termed lipolysis, is tightly regulated by hormones. Inhibition or activation of this process depends on the metabolic situation. In the postprandial phase, lipolysis is inhibited by insulin and WAT stores excess dietary FFA in the form of triglycerides (TG). In periods of increased energy demand, lipolysis is activated by hormonal (ß-adrenergic) stimulation and TG stores are hydrolyzed to provide fuel in the form of FFA. A dysregulation of WAT metabolism is associated with metabolic disorders such as lipodystrophy, obesity, type 2 diabetes, and metabolic syndrome. In industrialized countries, the incidence of obesity and related diseases has increased dramatically over the past 20 years. Therefore, it is of utmost importance to improve our understanding of the molecular processes controlling WAT function. The present project was focused on the function and on the regulation of adipose triglyceride lipase (ATGL). Our studies revealed that ATGL activity is essential for proper hormonal activation of lipolysis in adipocytes. In the absence of ATGL, lipolysis is reduced by approximately 70%. The enzyme initiates TG catabolism by removing the first fatty acid from the TG molecule. The generated diacylglycerol is subsequently hydrolyzed by hormone- sensitive lipase (HSL). Together, ATGL and HSL are responsible for more than 95% of the lipolytic activity present in WAT. Our major finding was that ATGL activity is stimulated by a protein termed CGI-58 or ABHD5 (comparative gene expression protein 58 or a/ß hydrolase domain containing protein 5). This observation provided the basis for the understanding of rare inherited human disease which is characterized by systemic TG accumulation. This disorder, known as Neutral Lipid Storage Disease (NLSD), is associated with mutations in the ATGL gene or in the CGI-58 gene. These mutations substantially reduce ATGL activity leading to TG accumulation in many tissues of NLSD patients.