The role of CGI-58 in lipid and energy metabolism

The catabolism of adipose tissue triglyceride (TG) stores and the release of free fatty acids into the circulation is the most important energy resource during periods of fastening or increased energy demand. Energy homeostasis is achieved when TG deposition and TG mobilization are balanced. Disequilibrium in this energy circuit can be associated with the development of metabolic disease like obesity, type 2 Diabetes and cachexia. TG mobilization and the release of free fatty acids into the circulation strongly depend on the catabolism of adipose tissue TG stores by endogenous lipases. For a long time it was assumed that hormone-sensitive lipase (HSL) is the major lipase in TG hydrolysis of adipose and non-adipose tissue TG stores. However, mice deficient for HSL were able to substantially mobilize their adipose tissue TG stores implicating for at least one additional lipase involved in adipose (and non-adipose) tissue TG catabolism. The discovery and biochemical analysis of Adipose Triglyceride Lipase (ATGL) in our laboratory and by two independent groups showed that this lipase exhibits strong TG hydrolytic activity. The targeted disruption of ATGL in mice by Haemmerle et al. (Science Vol. 312, 2006) implicated that ATGL is essential in mammalian TG catabolism: Mice deficient for ATGL showed TG accumulation within multiple tissues together with increased adipose depots. The massive TG accumulation within cardiac muscle caused a severe lipid induced myopathy and a premature death of the animals. In a recent study we demonstrate that efficient ATGL mediated TG hydrolysis requires cofactor CGI-58 ("comparative gene identification-58"). Mutations in the human CGI-58 gene are linked to the development of the Chanarin-Dorfman-Syndrome (CDS), a rare genetic disease causing massive TG accumulation within multiple tissues. The presence of CGI-58 enhanced ATGL TG hydrolysis several-fold. Furthermore, CGI-58 mutations observed in patients affected by CDS fail to activate ATGL TG hydrolysis. With regard to the essential role of ATGL in mammalian TG catabolism and the impact on CGI-58 for ATGL enzyme activity we propose that CGI-58 plays an important role in the control of TG mobilization and energy homeostasis. Divergences in the phenotype of ATGL-ko mice in relation to CDS implicate for additional ATGL-independent functions of CGI-58 in lipid and energy metabolism. The availability and analysis of CGI-58 deficient mice will strongly contribute to our understanding of the molecular mechanisms involved in TG mobilization and regulation of energy homeostasis. Additionally, this mouse model allows us to study the role of CGI-58 not only in the pathogenesis of CDS but also in the development of other lipid associated disorders.

The storage and mobilization of triacylglycerols (TG) from adipose tissue (AT) plays an important role in whole body energy homeostasis. Imbalances in this process are implicated in the development of metabolic disorders including obesity, Type 2 diabetes, cardiovascular disease and hepatic steatosis. Upon energy demand, TG are mobilized from white AT leading to the release of fatty acids (FA) and glycerol into the blood stream. The first and initial step in TG catabolism is catalyzed by adipose triglyceride lipase (ATGL) to generate diacylglycerol (DG) which is further hydrolyzed to monoacylglycerol by hormone-sensitive lipase. Our laboratory could show that efficient ATGL-mediated TG catabolism depends on a co-factor designated as comparative gene identification-58 (CGI-58), at least in ex vivo assays. The aim of the present project was to examine the in vivo and organ specific role of CGI-58 in lipid and energy metabolism. I) We could show that CGI-58 is critically required for the formation of a functional skin permeability barrier: Mice globally lacking CGI-58 showed a severe defect in the formation of the epidermal skin barrier leading to early death of CGI-58-deficient mice within a few hours after birth. Impaired epidermal TG catabolism of mice lacking CGI-58 was linked to a defect in the formation of acyl-ceramides, which are essential intermediates for the formation of a functional skin permeability barrier. The short life-span of mice globally lacking CGI-58 hindered the examination of the organ-specific role of CGI-58 in adult animals. Therefore we generated and characterized mice lacking CGI-58 exclusively in the liver, muscle, AT and brain. II) Mice lacking CGI-58 exclusively in the liver showed severe hepatic steatosis caused by impaired TG catabolism and PPAR-alpha activated gene expression whereas hepatic VLDL-TG synthesis was not affected. III) The lack of muscle CGI-58 caused marked TG accumulation in cardiac (and skeletal) muscle despite a marked increase in ATGL protein levels showing that muscle TG catabolism depends on the presence of both, CGI-58 and ATGL. IV) The lack of adipose CGI-58 provoked mild obesity and impaired TG mobilization from AT which interfered with the hepatic fasting response. V) Finally, the lack of CGI 58 in neurons provoked TG accumulation in the brain and affected whole body energy homeostasis. Taken together, the outcome of this project demonstrates that CGI-58 is an important regulator of TG catabolism in many organs including the skin, liver, muscle and AT thereby interfering with whole body energy homeostasis.