期刊
JOURNAL OF LIPID RESEARCH
卷 62, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.jlr.2021.100027
关键词
cholesteryl ester transfer protein; substrate specificity; HDL metabolism; hepatic gene expression; hepatic cholesterol; reverse cholesterol transport; cholesterol efflux; LCAT; SRBI; triglyceride
资金
- American Heart Association [16GRNT31000002]
- National Heart, Lung, and Blood Institute, National Institutes of Health [HL130041]
Research showed that modifying CETP's lipid substrate preference can selectively alter HDL concentration and function, providing a powerful tool for modulating HDL metabolism and impacting sterol balance in vivo.
Cholesteryl ester transfer protein (CETP) modulates lipoprotein metabolism by transferring cholesteryl ester (CE) and triglyceride (TG) between lipoproteins. However, differences in the way CETP functions exist across species. Unlike human CETP, hamster CETP prefers TG over CE as a substrate, raising questions regarding how substrate preference may impact lipoprotein metabolism. To understand how altering the CE versus TG substrate specificity of CETP might impact lipoprotein metabolism in humans, we modified CETP expression in fat/cholesterol-fed hamsters, which have a human-like lipoprotein profile. Hamsters received adenoviruses expressing no CETP, hamster CETP, or human CETP. Total plasma CETP mass increased up to 70% in the hamster and human CETP groups. Hamsters expressing human CETP exhibited decreased endogenous hamster CETP, resulting in an overall CE:TG preference of plasma CETP that was similar to that in humans. Hamster CETP overexpression had little impact on lipoproteins, whereas human CETP expression reduced HDL by 60% without affecting LDL. HDLs were TG enriched and CE depleted and much smaller, causing the HDL3:HDL2 ratio to increase threefold. HDL from hamsters expressing human CETP supported higher LCAT activity and greater cholesterol efflux. The fecal excretion of HDL-associated CE in human CETP animals was unchanged. However, much of this cholesterol accumulated in the liver and was associated with a 1.8-fold increase in hepatic cholesterol mass. Overall, these data show in a human-like lipoprotein model that modification of CETP's lipid substrate preference selectively alters HDL concentration and function. This provides a powerful tool for modulating HDL metabolism and impacting sterol balance in vivo.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据