Hepatic expression of scavenger receptor class B type I (SR-BI) is a positive regulator of macrophage reverse cholesterol transport in vivo

Abstract

Hepatic expression of the scavenger receptor class B type I (SR-BI) promotes selective uptake of HDL cholesterol by the liver and is believed to play a role in the process of reverse cholesterol transport (RCT). We hypothesized that hepatic SR-BI expression is a regulator of the rate of integrated macrophage-to-feces RCT and used an in vivo model to test this hypothesis. Cholesterol-loaded and [3H]cholesterol-labeled J774 macrophages were injected intraperitoneally into mice, after which the appearance of the [3H]cholesterol in the plasma, liver, and feces over 48 hours was quantitated. Mice overexpressing SR-BI in the liver had significantly reduced [3H]cholesterol in the plasma but markedly increased [3H] tracer excretion in the feces over 48 hours. Conversely, mice deficient in SR-BI had significantly increased [3H]cholesterol in the plasma but markedly reduced [3H] tracer excretion in the feces over 48 hours. These studies demonstrate that hepatic SR-BI expression, despite its inverse effects on steady-state plasma HDL cholesterol concentrations, is an important positive regulator of the rate of macrophage RCT.

Figure 1

Macrophage RCT in SR-BI–overexpressing mice. Mice were injected intravenously with SR-BI adenovirus or control adenovirus and then 3 days later injected intraperitoneally with [³H]-labeled cholesterol J774 foam cells. (A) [³H]cholesterol in plasma, liver, and feces of C57BL/6 mice (n = 6 per group). (B) [³H]cholesterol in plasma, liver, and feces of apoA-I–transgenic mice (n = 6 per group). (C) Cholesterol mass and [³H]cholesterol lipoprotein profile of pooled plasma samples drawn 24 hours after injection of J774 cells from apoA-I–transgenic mice subjected to FPLC analysis. *P < 0.05; **P < 0.01.

Figure 2

Macrophage RCT in SR-BI–knockout mice. SR-BI^–/– mice and wild-type littermates were injected intraperitoneally with [³H]cholesterol-labeled J774 foam cells in 2 independent experiments and results pooled for analysis (n = 11 per group). (A) [³H]cholesterol in plasma, liver, and feces. (B) Cholesterol mass and [³H]cholesterol lipoprotein profile of pooled plasma samples drawn 24 hours after injection of J774 cells subjected to FPLC analysis. *P < 0.05; **P < 0.01.