Inflammation Impairs Reverse Cholesterol Transport In Vivo

被引:315
作者
McGillicuddy, Fiona C. [2 ]
Moya, Margarita de la Llera [3 ]
Hinkle, Christine C. [2 ]
Joshi, Michelle R.
Chiquoine, Elise H. [2 ]
Billheimer, Jeffrey T. [2 ]
Rothblat, George H. [3 ]
Reilly, Muredach P. [1 ,2 ]
机构
[1] Univ Penn, Med Ctr, Cardiovasc Inst, Sch Med, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA
[3] Childrens Hosp Philadelphia, Gastrointestinal & Nutr Div, Philadelphia, PA 19104 USA
关键词
atherosclerosis; cholesterol; inflammation; lipoproteins; macrophages; APOLIPOPROTEIN-A-I; HIGH-DENSITY-LIPOPROTEIN; B TYPE-I; MESSENGER-RNA LEVELS; ACUTE-PHASE HDL; PHOSPHOLIPASE A(2); ENDOTHELIAL LIPASE; SR-BI; ENDOTOXIN; MACROPHAGES;
D O I
10.1161/CIRCULATIONAHA.108.810721
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 and Results 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 H-3-cholesterol movement from macrophage to plasma and H-3-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 H-3-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. (Circulation. 2009; 119: 1135-1145.)
引用
收藏
页码:1135 / U121
页数:26
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