Role of intestinal ATGL in lipid absorption and metabolic disorders

The increased incidence of metabolic disorders and cardiovascular diseases during the last decades are linked to an increase in dietary fat intake. Marked and prolonged postprandial hypertriglyceridemia, characterized by the accumulation of triacylglycerol (TG)-rich lipoproteins, is a significant contributor to the development of dyslipidemia and a known risk factor for atherosclerosis. Enterocytes in the small intestine transfer dietary lipids to the organism and largely contribute to TG-rich lipoprotein production. In the gut, TG are hydrolyzed to generate free fatty acids and monoacylglycerol by pancreatic lipase. These products are then taken up by the enterocytes and are re-esterified into TG, incorporated into chylomicrons and secreted into the circulation. So far it is unclear whether re-synthesized TG are stored in enterocytes as cytoplasmic lipid droplets and whether enterocytes possess lipolytic enzymes that promote TG hydrolysis. Adipose TG lipase (ATGL) is the rate-limiting enzyme in the first step of TG hydrolysis which results in the formation of diacylglycerol and fatty acids. ATGL was shown to be essential for efficient TG metabolism in adipose and non-adipose tissues. Whole body ATGL knock-out (ATGL-KO) mice accumulate TG also in the small intestine indicating that ATGL might be involved in the hydrolysis of TG in enterocytes. Our preliminary findings suggest that ATGL is highly expressed in the small intestine. Subsequently, we have preparatory data suggesting that ATGL deficiency resulted in decreased TG hydrolysis, increased TG accumulation and decreased TG absorption. To elucidate the role of intestinal ATGL, we will generate mice which lack ATGL exclusively in the small intestine. These mice will be used to study the impact of intestinal ATGL on plasma lipid metabolism, on dietary fat absorption, on intestinal lipoprotein secretion, on lymphatic lipoprotein size and composition, on body weight and body composition, and on the development of insulin resistance and obesity. The aims of the project are to understand the mechanisms how ATGL controls lipid absorption, synthesis and secretion of TG-rich lipoproteins in enterocytes. Specifically, the following questions will be addressed: " Is intestinal ATGL involved in the hydrolysis of the TG storage pool? " Is intestinal ATGL involved in TG absorption? " Does intestinal ATGL affect postprandial lipemia? " Which genes are differentially regulated in the absence of ATGL in intestinal cells? " Does intestinal ATGL play an important role in the development of insulin resistance and obesity? Results from the proposed application might lead to the identification of new drug targets enabling pharmacological intervention for reduction of intestinal dietary lipid flux and postprandial hypertriglyceridemia.

The increased incidence of metabolic disorders and cardiovascular diseases during the last decades are linked to an increase in dietary fat intake. In Austria, more than 50% of the population is obese and the percentage of overweight individuals is 10-15% with progressively increasing tendency. Obesity and related diseases (e.g. type 2 diabetes, cardiovascular diseases, atherosclerosis, fatty liver disease) are a big and costly health problem. According to estimations by the WHO, ~ 146 million people worldwide suffer from type 2 diabetes. In this respect, an excessive and prolonged postprandial hypertriglyceridemia, characterized by the accumulation of triacylglycerol (TG)-rich lipoproteins, has been recognized as a predictor of systemic dyslipidemia and a known risk factor for atherosclerosis. Importantly, despite all pathological aspects of alterations in the systemic lipid metabolism, plasma lipid concentrations are primarily determined by dietary fat absorption in the small intestine. The small intestine is a crucial player in whole body lipid homeostasis due to its ability to regulate energy intake. In this project, we elucidated the role of 2 enzymes (ATGL and HSL) in the small intestine by generating mice with an intestinal lack of HSL or ATGL, respectively. Intestinal HSL knock out (HSLiKO) mice exhibit increased cholesteryl ester concentrations in the gut. Lipid absorption studies revealed that HSLiKO mice have accelerated cholesterol but unchanged fat absorption. In contrast, we found increased intracellular fat content in intestinal ATGL knock out (ATGLiKO) small intestines. Our results show that ATGL mobilizes fatty acids from the systemic circulation absorbed by the gut. In summary, we found that both lipases play a critical role in intestinal lipid metabolism. Whereas intestinal HSL deficiency mainly changes cholesterol metabolism (i.e. cholesteryl ester concentrations and the rate of cholesterol absorption), intestinal ATGL deficiency results in fat accumulation. Due to the absence of important metabolites, uptake of fatty acids and cholesterol is altered. Our results improved our understanding about the mechanisms of dietary fat absorption, demonstrating that at least one enzyme involved in TG absorption is still elusive. This might eventually lead to the identification of new drug targets enabling pharmacological intervention for reduction of intestinal dietary lipid flux and postprandial hypertriglyceridemia.