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The lipid substrate preference of CETP controls the biochemical properties of HDL in fat/cholesterol-fed hamsters

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, raisin...

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Autores principales: Morton, Richard E., Mihna, Daniel, Liu, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933494/
https://www.ncbi.nlm.nih.gov/pubmed/33515552
http://dx.doi.org/10.1016/j.jlr.2021.100027
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author Morton, Richard E.
Mihna, Daniel
Liu, Yan
author_facet Morton, Richard E.
Mihna, Daniel
Liu, Yan
author_sort Morton, Richard E.
collection PubMed
description 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.
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spelling pubmed-79334942021-03-19 The lipid substrate preference of CETP controls the biochemical properties of HDL in fat/cholesterol-fed hamsters Morton, Richard E. Mihna, Daniel Liu, Yan J Lipid Res Research Article 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. American Society for Biochemistry and Molecular Biology 2021-01-27 /pmc/articles/PMC7933494/ /pubmed/33515552 http://dx.doi.org/10.1016/j.jlr.2021.100027 Text en © 2021 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Article
Morton, Richard E.
Mihna, Daniel
Liu, Yan
The lipid substrate preference of CETP controls the biochemical properties of HDL in fat/cholesterol-fed hamsters
title The lipid substrate preference of CETP controls the biochemical properties of HDL in fat/cholesterol-fed hamsters
title_full The lipid substrate preference of CETP controls the biochemical properties of HDL in fat/cholesterol-fed hamsters
title_fullStr The lipid substrate preference of CETP controls the biochemical properties of HDL in fat/cholesterol-fed hamsters
title_full_unstemmed The lipid substrate preference of CETP controls the biochemical properties of HDL in fat/cholesterol-fed hamsters
title_short The lipid substrate preference of CETP controls the biochemical properties of HDL in fat/cholesterol-fed hamsters
title_sort lipid substrate preference of cetp controls the biochemical properties of hdl in fat/cholesterol-fed hamsters
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933494/
https://www.ncbi.nlm.nih.gov/pubmed/33515552
http://dx.doi.org/10.1016/j.jlr.2021.100027
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