Pancreatic lipolytic enzymes in lipid absorption and intestinal lipoprotein biosynthesis:

Dietary intake of cholesterol is associated with fat consumption. The process of fat digestion and emulsification begins in the stomach with partial fat digestion by preduodenal lipases and emulsification by peristalsis. The crude emulsions are then delivered to the duodenum where they are mixed with bile and pancreatic juices. In the lumen of the intestine, free cholesterol is associated with triglycerides and phospholipids in lipid emulsions, mixed with phospholipids and bile salts in micelles, and complexed with phospholipid vesicles. It is generally believed that enzymatic digestion of these lipid substrates is required prior to fat and cholesterol absorption by the intestinal mucosa. Lipid digestion in the intestinal lumen is mediated by pancreatic lipolytic enzymes including carboxyl ester lipase (CEL, previously called cholesterol esterase), pancreatic triglyceride lipase (PTL), and the group 1B phospholipase A₂ (PLA₂1B). Our laboratory has generated 3 knockout mouse lines, each defective in expression of one of these enzymes, to assess their unique contribution to the lipid digestion and absorption process. Our results showed that CEL does not play a major role in lipid digestion. However, this enzyme is important in mediating intestinal lipoprotein assembly and secretion. Our working hypothesis, as supported by preliminary data, is that CEL modulate ceramide levels in the intestine and alter intracellular cholesterol trafficking to compartments necessary for chylomicron assembly and secretion. Interestingly, studies of PTL-knockout mice revealed that PTL is not the only enzyme capable of triglyceride hydrolysis in intestinal lumen and the PTL-null mice are fully capable of triglyceride digestion and fat absorption. Interestingly, PTL-null mice have significantly reduced cholesterol absorption capacity. We postulate that the reduced cholesterol absorption as a consequence of delayed lipid digestion in the proximal intestine is due to differences in transport protein expression in the brush border of proximal and distal intestine. Our results with PLA₂1B-null mice also showed additional enzyme(s) in the intestinal lumen capable of phospholipid hydrolysis and that the PLA₂1B may have pleiotropic functions in vivo in both lipid digestion and controlling insulin sensitivity. Current projects in this area of research include:

1) Identify the mechanism by which CEL promotes lipid absorption and intestinal lipoprotein assembly, testing the hypothesis that CEL influences lipid signaling pathways that are important for proper intracellular lipid transport.

2)  Identify the mechanism by which delayed lipid digestion in the proximal intestine results in overall suppression of cholesterol absorption in PTL-deficient mice.

3)  Identify the compensatory enzymes in the digestive tract for triglyceride and phospholipid hydrolysis. 

The information gained from these studies will help identify novel treatment strategy to reduce dietary lipid absorption and suppress diet-induced hyperlipidemia and the risk of lipid-related diseases.