Abstract
Neutral cholesteryl ester hydrolase (CEH)-mediated hydrolysis of cellular cholesteryl esters (CEs) is required not only to generate free cholesterol (FC) for efflux from macrophages but also to release FC from lipoprotein-delivered CE in the liver for bile acid synthesis or direct secretion into the bile. We hypothesized that hepatic expression of CEH would regulate the hydrolysis of lipoprotein-derived CE and enhance reverse cholesterol transport (RCT). Adenoviral-mediated CEH overexpression led to a significant increase in bile acid output. To assess the role of hepatic CEH in promoting flux of cholesterol from macrophages to feces, cholesterol-loaded and [3H]cholesterol-labeled J774 macrophages were injected intraperitoneally into mice and the appearance of [3H]cholesterol in gallbladder bile and feces over 48 h was quantified. Mice overexpressing CEH had significantly higher [3H]cholesterol radiolabel in bile and feces, and it was associated with bile acids. This CEH-mediated increased movement of [3H]cholesterol from macrophages to bile acids and feces was significantly attenuated in SR-BI(-/-) mice. These studies demonstrate that similar to macrophage CEH that rate-limits the first step, hepatic CEH regulates the last step of RCT by promoting the flux of cholesterol entering the liver via SR-BI and increasing hepatic bile acid output.
Highlights
Neutral cholesteryl ester hydrolase (CEH)mediated hydrolysis of cellular cholesteryl esters (CEs) is required to generate free cholesterol (FC) for efflux from macrophages and to release FC from lipoproteindelivered CE in the liver for bile acid synthesis or direct secretion into the bile
The highest hepatic CEH expression with no hepatic toxicity was observed in mice injected with 108 pfu/ml, and this dose was used for all subsequent experiments
We demonstrate that hepatic CEH expression has a direct and substantial effect on bile acid secretion and elimination of cholesterol from the body as bile acids
Summary
Neutral cholesteryl ester hydrolase (CEH)mediated hydrolysis of cellular cholesteryl esters (CEs) is required to generate free cholesterol (FC) for efflux from macrophages and to release FC from lipoproteindelivered CE in the liver for bile acid synthesis or direct secretion into the bile. Mice overexpressing CEH had significantly higher [3H]cholesterol radiolabel in bile and feces, and it was associated with bile acids. Reverse cholesterol transport (RCT) is the primary mechanism for the removal of excess cholesterol from the peripheral tissues, including artery wall-associated macrophage foam cells [5]. This process is initiated and ratelimited by intracellular CE hydrolysis catalyzed by neutral cholesteryl ester hydrolase (CEH) that releases the unesterified or free cholesterol (FC) [6]. In vivo RCT and elimination of cholesterol from the body into bile and feces was significantly higher from macrophages with transgenic expression of CEH, establishing its role in regulating the first step of RCT. On the other hand, overexpression of neutral CEH leads to an increase in bile acid synthesis [12]
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