Inflammation impairs reverse cholesterol transport in vivo.
Circulation
; 119(8): 1135-45, 2009 Mar 03.
Article
em En
| MEDLINE
| ID: mdl-19221221
ABSTRACT
BACKGROUND:
Inflammation is proposed to impair reverse cholesterol transport (RCT), a major atheroprotective function of high-density lipoprotein (HDL). The present study presents the first integrated functional evidence that inflammation retards numerous components of RCT. METHODS ANDRESULTS:
We used subacute endotoxemia in the rodent macrophage-to-feces RCT model to assess the effects of inflammation on RCT in vivo and performed proof of concept experimental endotoxemia studies in humans. Endotoxemia (3 mg/kg SC) reduced (3)H-cholesterol movement from macrophage to plasma and (3)H-cholesterol associated with HDL fractions. At 48 hours, bile and fecal counts were markedly reduced consistent with downregulation of hepatic expression of ABCG5, ABCG8, and ABCB11 biliary transporters. Low-dose lipopolysaccharide (0.3 mg/kg SC) also reduced bile and fecal counts, as well as expression of biliary transporters, but in the absence of effects on plasma or liver counts. In vitro, lipopolysaccharide impaired (3)H-cholesterol efflux from human macrophages to apolipoprotein A-I and serum coincident with reduced expression of the cholesterol transporter ABCA1. During human (3 ng/kg; n=20) and murine endotoxemia (3 mg/kg SC), ex vivo macrophage cholesterol efflux to acute phase HDL was attenuated.CONCLUSIONS:
We provide the first in vivo evidence that inflammation impairs RCT at multiple steps in the RCT pathway, particularly cholesterol flux through liver to bile and feces. Attenuation of RCT and HDL efflux function, independent of HDL cholesterol levels, may contribute to atherosclerosis in chronic inflammatory states including obesity, metabolic syndrome, and type 2 diabetes.
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Base de dados:
MEDLINE
Assunto principal:
Colesterol
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Endotoxemia
Limite:
Adolescent
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Adult
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Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Circulation
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos