Potential beneficial effects of intestinal ATGL overexpression

The increased incidence of metabolic disorders and cardiovascular diseases during the last decades are mainly 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 and cholesterol-rich lipoprotein production. In the gut, TG are hydrolyzed by pancreatic lipase to generate free fatty acids (FFAs) and monoacylglycerol. These products are then taken up by the enterocytes, re-esterified into TG, incorporated into chylomicrons, and secreted into the circulation. Adipose triglyceride lipase (ATGL) is essential for efficient TG metabolism in adipose and non-adipose tissues. We have recently shown that intestine-specific ATGL knockout mice accumulate TG in the small intestine. Our results provide evidence that ATGL itself does not provide FFAs for TG resynthesis and chylomicron production but generates lipid mediators important for peroxisome proliferator-activated receptor (PPAR)a signaling. Moreover, our findings highlighted the presence of a TG hydrolase that is essential for TG absorption in the small intestine which is still elusive. The aims of this project are to understand the role of ATGL in the small intestine in more detail and whether its activation has beneficial effects with regard to lipid homeostasis. By generating mice with specific overexpression of ATGL in the small intestine we will answer whether: - ATGL overexpression modulates intestinal lipid composition - ATGL overexpression improves PPARa signaling and -oxidation - ATGL overexpression reduces TG and cholesterol absorption - ATGL overexpression protects from obesity and hyperlipidemia. To increase the impact of this project on the field we also aim at identifying the so far unknown lipase(s) involved in TG absorption in the small intestine. Results from the proposed application are expected to improve our understanding of the mechanisms of dietary fat absorption and the potential beneficial effects of intestinal ATGL hyperactivation. Our findings might lead to the identification of ATGL and/or the lipase(s) involved in TG absorption as new drug target(s) enabling pharmacological intervention for reduction of intestinal dietary lipid flux, postprandial hypertriglyceridemia, and cholesterol absorption.

The increased frequency of metabolic and cardiovascular diseases in the last decades is mainly linked to an increased intake of dietary lipids (fats). Overweight and obesity with its sequelae such as atherosclerosis, type 2 diabetes and fatty liver are a costly health problem in the Western societies. Prolonged hypertriglyceridemia is one of the most prominent risk factors for cardiovascular diseases and is characterized by the accumulation of triglyceride- rich lipoproteins in the blood. Specialized cells of the small intestine (enterocytes) play a crucial role in maintaining whole body fat homeostasis by mediating dietary lipid uptake and ensuring the supply of fatty acids to other organs. Complex lipids (triglycerides) from the diet are hydrolyzed by lipid hydrolases in the intestinal lumen into smaller molecules, which are taken up by enterocytes and converted again into triglycerides. These newly synthesized triglycerides are either secreted into the blood or stored in form of cytosolic lipid droplets within the cell. Since lipid droplets become smaller in the postprandial phase, triglyceride hydrolysis likely sustains fat supply during fasting periods. This project investigated the role of a specific lipid hydrolase (ATGL) in the small intestine. We demonstrated that lipid hydrolysis in the small intestine is by far more complex than described in previous models, highlighting the necessity to modify the current model of intestinal lipid metabolism. We found that ATGL contributed to the hydrolysis of re-absorbed lipids from the blood but not to the catabolism of dietary lipids, rendering this type of enzyme still elusive. We used a sophisticated screening strategy to identify additional potential lipid hydrolases in the small intestine. Their contributions in intestinal fat homeostasis, however, need to be evaluated in the future. Further studies in this field should lead to novel therapeutic treatments for the reduction of fat content in the intestine and the blood.