Structure-function relationship of carboxyl ester lipase (CEL) and its role in atherosclerosis:

A long standing interest of our laboratory is to understand the structure-function relationship as well as the role of CEL in lipid metabolism and atherosclerosis. During the course of our investigations, we found that, in addition to its expression in the gastrointetsinal tract where it participates in intestinal lipoprotein assembly and secretion, CEL is also synthesized in human endothelial cells and monocyte/macrophages in a manner that is inducible by oxidized LDL (oxLDL). We also demonstrated that CEL is capable of hydrolyzing lysophospholipids and ceramides in addition to its activity against cholesterol esters. Finally, we found that the human CEL gene is highly polymorphic with a variable region dictating the number of proline-rich repeating units in the carboxyl-terminal end of the protein. Based on these recent novel observations, our current research in this area is focused on testing three hypotheses:

1) Carboxyl ester lipase expression in the vasculature is an inflammatory response mechanism that protects early stages of atherogenesis by hydrolyzing and reducing the atherogenic properties of lysophospholipids and ceramide generated as a result of LDL oxidation.

2) The number of proline-rich repeating units at the carboxyl-terminus of CEL is important in dictating the ability of human CEL to hydrolyze lysophospholipids and ceramide in a bile salt-independent manner.

3) Genetic polymorphism at the CEL locus is a useful predictor for the risk of premature atherosclerosis.

Taken together, these studies will offer insights into novel mechanisms, independent of cholesterol deposition, that contribute to atherosclerosis.  These studies will also help to identify subjects at risk for premature and contribute information toward designing therapeutic regimen to minimize their risk.