Intracellular cholesterol transport proteins enhance hydrolysis of HDL-CEs and facilitate elimination of cholesterol into bile

Jing Wang,Jinghua Bie,Shobha Ghosh

doi:10.1194/jlr.m069682

Jing Wang, Jinghua Bie + Show 1 more

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https://doi.org/10.1194/jlr.m069682

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Abstract

While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood. In the present study, we examined the hypothesis that intracellular cholesterol transport proteins [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 (FABP1)] not only facilitate CE hydrolase-mediated hydrolysis of HDL-CEs, but also enhance elimination of cholesterol into bile. Adenovirus-mediated overexpression of FABP1 or SCP2 in primary hepatocytes significantly increased hydrolysis of HDL-[(3)H]CE, reduced resecretion of HDL-CE-derived FC as nascent HDL, and increased its secretion as bile acids. Consistently, the flux of [(3)H]cholesterol from HDL-[(3)H]CE to biliary bile acids was increased by overexpression of SCP2 or FABP1 in vivo and reduced in SCP2(-/-) mice. Increased flux of HDL-[(3)H]CE to biliary FC was noted with FABP1 overexpression and in SCP2(-/-) mice that have increased FABP1 expression. Lack of a significant decrease in the flux of HDL-[(3)H]CE to biliary FC or bile acids in FABP1(-/-) mice indicates the likely compensation of its function by an as yet unidentified mechanism. Taken together, these studies demonstrate that FABP1 and SCP2 facilitate the preferential movement of HDL-CEs to bile for final elimination.

Highlights

While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood
Expression of SR-BI was critical for this process and CE hydrolase (CEH)-dependent increase in hydrolysis of HDL-CE was attenuated in SR-BI / mice or hepatocytes [3]
It should be noted that fold increase in expression of sterol carrier protein 2 (SCP2) or fatty acid binding protein-1 (FABP1) could not be calculated because species-specific TaqMan assays were used and no Ct value was obtained in control Ad-LacZ-transduced mouse hepatocytes compared with Ct values ranging from 23 to 25 for hepatocytes transduced with human Ad-SCP2 or Ad-FABP1 viruses, indicating increased expression

Summary

Introduction

While HDL-associated unesterified or free cholesterol (FC) is thought to be rapidly secreted into the bile, the fate of HDL-associated cholesteryl esters (HDL-CEs) that represent >80% of HDL-cholesterol, is only beginning to be understood. We examined the hypothesis that intracellular cholesterol transport proteins [sterol carrier protein 2 (SCP2) and fatty acid binding protein-1 (FABP1)] facilitate CE hydrolase-mediated hydrolysis of HDL-CEs, and enhance elimination of cholesterol into bile. Lack of a significant decrease in the flux of HDL-[3H]CE to biliary FC or bile acids in FABP1 / mice indicates the likely compensation of its function by an as yet unidentified mechanism Taken together, these studies demonstrate that FABP1 and SCP2 facilitate the preferential movement of HDL-CEs to bile for final elimination.—Wang, J., J. HDL-derived cholesterol (FC or FC generated after CEH-mediated hydrolysis of HDL-CE) can potentially have multiple fates within the hepatocyte It can either be resecreted as part of nascent HDL or VLDL following esterification; the two processes that will not facilitate the final elimination of cholesterol from the body.

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