Carboxyl ester lipase

Abstract

Carboxyl ester lipase (CEL), previously named cholesterol esterase or bile salt-stimulated (or dependent) lipase, is a lipolytic enzyme capable of hydrolyzing cholesteryl esters, tri-, di-, and mono-acylglycerols, phospholipids, lysophospholipids, and ceramide. The active site catalytic triad of serine-histidine-aspartate is centrally located within the enzyme structure and is partially covered by a surface loop. The carboxyl terminus of the protein regulates enzymatic activity by forming hydrogen bonds with the surface loop to partially shield the active site. Bile salt binding to the loop domain frees the active site for accessibility by water-insoluble substrates. CEL is synthesized primarily in the pancreas and lactating mammary gland, but the enzyme is also expressed in liver, macrophages, and in the vessel wall. In the gastrointestinal tract, CEL serves as a compensatory protein to other lipolytic enzymes for complete digestion and absorption of lipid nutrients. Importantly, CEL also participates in chylomicron assembly and secretion, in a mechanism mediated through its ceramide hydrolytic activity. Cell culture studies suggest a role for CEL in lipoprotein metabolism and oxidized LDL-induced atherosclerosis. Thus, this enzyme, which has a wide substrate reactivity and diffuse anatomic distribution, may have multiple functions in lipid and lipoprotein metabolism, and atherosclerosis. Carboxyl ester lipase (CEL), previously named pancreatic cholesterol esterase and also known as bile salt-stimulated (or -dependent) lipase, is a nonspecific lipolytic enzyme capable of hydrolyzing cholesteryl esters, tri-, di-, and mono-acylglycerols, phospholipids, lysophospholipids, and ceramide (1-3). The hydrolysis of water-insoluble carboxyl esters with long chain fatty acyl groups by CEL requires its activation by bile salt. However, CEL hydrolysis of water-soluble substrates such as carboxyl esters with short chain fatty acids or lysophospholipids does not have an absolute dependence on bile salt activation. The CEL protein is synthesized primarily in the pancreatic acinar cells and lactating mammary glands of higher mammals. Small amounts of CEL are found in other tissues, particularly the liver, macrophages, endothelial cells, and eosinophils (4-10). Extensive research has been performed in recent years on the structure-function relationship of this protein as well as its physiological role in lipid metabolism. A significant body of work has also been devoted to studying CEL processing and transport in pancreatic acinar cells. The latter topic was reviewed recently (11) and will be discussed only briefly in this article when appropriate. This article will present an updated review on the structure-function studies of CEL as well as an in-depth discussion on the current understanding of its role in lipid metabolism. PROTEIN STRUCTURE-FUNCTION RELATIONSHIP Active siteThe nucleotide sequence of CEL from various species shows that it is a highly conserved protein belonging to the ␣ / ␤ hydrolase family. The carb...

Carboxyl Ester Lipase Cofractionates with Scavenger Receptor BI in Hepatocyte Lipid Rafts and Enhances Selective Uptake and Hydrolysis of Cholesteryl Esters from HDL3

“…Concentrations in portal blood are typically 6 times higher than in peripheral circulation. The K d for bile salt binding to CEL is ϳ20 M, and it is enzymatically active at approximately this same concentration (37,42). The high bile salt concentrations (ϳ10 mM) present in intestine and typically used with CEL in vitro are important for substrate solubility, not enzyme activity.…”

Pancreatic Function in Carboxyl-Ester Lipase Knockout Mice

“…The variability of the VNTR between species is high, with three repeats in mice. It has been clearly demonstrated that truncation of the C-terminal domain does not affect the enzymatic activity of CEL, although the interaction with bile salt may be compromised [34]. In spite of these differences, CEL is expressed at comparable levels in the exocrine pancreas in both mouse and human [33].…”

Ceramide-induced Intracellular Oxidant Formation, Iron Signaling, and Apoptosis in Endothelial Cells

“…Altered lipid metabolism resulting in elevated ceramide levels and increased oxidative stress had been implicated in atherosclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease (46,49,50). The ceramide-induced ROSmediated apoptotic signaling pathway has been suggested to play a key role in the degeneration of dopaminergic neurons in patients with Parkinson's disease (7,12).…”