Virtually, every cell of the body is capable to deposit triglycerides (TG) in more or less quantities. Fatty acids (FA) are an important energy fuel in mammals and FA utilized as energy substrate or signaling molecule may originate from cellular uptake or the catabolism of endogenous TG deposits. Imbalances in cellular TG homeostasiscan be linked to metabolic disease development. Studies from our laboratory and others demonstrated that cellular TG catabolism, also referred to as lipolysis, is a three-step process catalyzed by Adipose triglyceride lipase (ATGL), Hormone-sensitive lipase and Monoglyceride lipase. ATGL activity requires the co-factor Comparative-gene identification-58 (CGI-58). Deficiency of ATGL or CGI-58 divergently affects organ TG homeostasis and function. Humans (and mice) lacking ATGL develop severe cardiac steatosis and heart dysfunction, which can be lethal. FA generated by ATGL-mediated TG hydrolysis serve not only as energy substrate but also as ligands or ligand precursors for PPARalpha-driven expression of genes implicated in mitochondrial FA oxidation. In contrast, CGI-58 deficiency leads to a severe skin barrier defect and steatohepatitis. Notably, the lack of either CGI-58 or ATGL in the liver is compatible with normal lipoprotein TG production indicating that hepatic TG mobilization destined for lipoprotein TG synthesis involves a currently unknown TG lipase(s).

In a very recent study, we show that a member of the Carboxylesterase 2 (Ces2) family efficiently hydrolyses TG and diglycerides. Intestine-specific overexpression of murine Ces2c interfered with whole body TG homeostasis and the transgenic mice were resistant towards diet-induced hepatic steatosis. Moreover, cardiac-muscle specific overexpression of Perilipin 5 (Plin5), a binding partner of CGI-58 and ATGL, leads to massive TG accumulation in the heart of transgenic mice via the formation of a lipolytic barrier. Unexpectedly, cardiac steatosis was compatible with normal heart function and life span in Plin5 transgenic mice. Actually, we are interested in the functional role of lipid droplet-associated proteins in the regulation of cardiac lipolysis and lipid signaling. Furthermore, we investigate the role of Ces2 proteins in hepatic and intestinal lipid metabolism.

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