Endogenous cholesterol ester hydroperoxides modulate cholesterol levels and inhibit cholesterol uptake in hepatocytes and macrophages.
Aged
Animals
Biomarkers
Cardiovascular Diseases
Cholesterol
/ metabolism
Cholesterol Esters
/ genetics
Chromatography, Liquid
Disease Models, Animal
Female
Hepatocytes
/ metabolism
Humans
Lipid Metabolism
Liver X Receptors
/ metabolism
Macrophages
/ metabolism
Male
Mass Spectrometry
Metabolome
Mice
Middle Aged
Receptors, LDL
/ metabolism
CVD
Cholesterol ester hydroperoxides
Cholesterol uptake
Cholesterol/metabolism
LDL oxidation
LDLR
LXR
Lipid peroxidation
Lipidomics
Journal
Redox biology
ISSN: 2213-2317
Titre abrégé: Redox Biol
Pays: Netherlands
ID NLM: 101605639
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
15
11
2018
accepted:
06
12
2018
pubmed:
24
12
2018
medline:
4
4
2019
entrez:
22
12
2018
Statut:
ppublish
Résumé
Dysregulation of cholesterol metabolism represents one of the major risk factors for atherosclerotic cardiovascular disease (CVD). Oxidized cholesterol esters (oxCE) in low-density lipoprotein (LDL) have been implicated in CVD but the underlying mechanisms remain poorly defined. We use a targeted lipidomic approach to demonstrate that levels of oxCEs in human plasma are associated with different types of CVD and significantly elevated in patients with myocardial infarction. We synthesized a major endogenous cholesterol ester hydroperoxide (CEOOH), cholesteryl-13(cis, trans)-hydroperoxy-octadecadienoate (ch-13(c,t)-HpODE) and show that this endogenous compound significantly increases plasma cholesterol level in mice while decrease cholesterol levels in mouse liver and peritoneal macrophages, which is primarily due to the inhibition of cholesterol uptake in macrophages and liver. Further studies indicate that inhibition of cholesterol uptake by ch-13(c,t)-HpODE in macrophages is dependent on LXRα-IDOL-LDLR pathway, whereas inhibition on cholesterol levels in hepatocytes is dependent on LXRα and LDLR. Consistently, these effects on cholesterol levels by ch-13(c,t)-HpODE are diminished in LDLR or LXRα knockout mice. Together, our study provides evidence that elevated plasma cholesterol levels by CEOOHs are primarily due to the inhibition of cholesterol uptake in the liver and macrophages, which may play an important role in the pathogenesis of CVD.
Identifiants
pubmed: 30576926
pii: S2213-2317(18)31085-1
doi: 10.1016/j.redox.2018.101069
pmc: PMC6302155
pii:
doi:
Substances chimiques
Biomarkers
0
Cholesterol Esters
0
Liver X Receptors
0
Receptors, LDL
0
cholesteryl ester hydroperoxide
2058-59-5
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
101069Informations de copyright
Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.
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