ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma

作者：Annema Wijtske; Dikkers Arne; de Boer Jan Freark; Gautier Thomas; Rensen Patrick C N; Rader Daniel J; Tietge Uwe J F^*

来源：The Journal of Lipid Research, 2012, 53(5): 929-940.

DOI：10.1194/jlr.M020743

• apolipoprotein E
• reverse cholesterol transport
• ATP-binding cassette transporter A1
• atherosclerosis
• bile
• cholesteryl ester transfer protein
• feces
• high density lipoprotein
• liver
• macrophage
• metabolism
• mice
• probucol

ApoE plays an important role in lipoprotein metabolism. This study investigated the effects of adenovirus-mediated human apoE overexpression (AdhApoE3) on sterol metabolism and in vivo reverse cholesterol transport (RCT). In wild-type mice, AdhApoE3 resulted in decreased HDL cholesterol levels and a shift toward larger HDL in plasma, whereas hepatic cholesterol content increased (P %26lt; 0.05). These effects were dependent on scavenger receptor class B type I (SR-BI) as confirmed using SR-BI-deficient mice. Kinetic studies demonstrated increased plasma HDL cholesteryl ester catabolic rates (P %26lt; 0.05) and higher hepatic selective uptake of HDL cholesteryl esters in AdhApoE3-injected wild-type mice (P %26lt; 0.01). However, biliary and fecal sterol output as well as in vivo macrophage-to-feces RCT studied with H-3-cholesterol-loaded mouse macrophage foam cells remained unchanged upon human apoE overexpression. Similar results were obtained using hApoE3 overexpression in human CETP transgenic mice. However, blocking ABCA1-mediated cholesterol efflux from hepatocytes in AdhApoE3-injected mice using probucol increased biliary cholesterol secretion (P %26lt; 0.05), fecal neutral sterol excretion (P %26lt; 0.05), and in vivo RCT (P %26lt; 0.01), specifically within neutral sterols.jlr These combined data demonstrate that systemic apoE overexpression increases i) SR-BI-mediated selective uptake into the liver and ii) ABCA1-mediated efflux of RCT-relevant cholesterol from hepatocytes back to the plasma compartment, thereby resulting in unchanged fecal mass sterol excretion and overall in vivo RCT.-Annema, W., A. Dikkers, J. F. de Boer, T. Gautier, P. C. N. Rensen, D. J. Rader, and U. J. F. Tietge. ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma. J. Lipid Res. 2012. 53: 929-940.

• 出版日期2012-5