.. DISCUSSION The results of this study demonstrate that SR-BI expression affects hepatic VLDL currently production with decreased VLDL-TG as well as VLDL-apoB production in SR-BI knockout mice and increased VLDL production in response to adenoviral SR-BI overexpression. Our data further indicate that HDL-derived cholesterol taken up via SR-BI can be packaged into VLDL particles and secreted by the liver, thereby pointing toward a potential intrahepatic metabolic shunt between HDL and apoB-containing lipoproteins. SR-BI is well characterized as a receptor mediating the selective uptake of cholesteryl ester from HDL into cells (1, 2). It has also been established by in vitro as well as in vivo studies that SR-BI and its human ortholog Cla-1 can bind apoB-containing lipoproteins and mediate their internalization (3�C6, 20).

This property of SR-BI might depend on the physiological context as hepatic overexpression of SR-BI in hapoB transgenic mice (21) or attenuated expression in LDLR knockout (22) mice did not affect the LDL catabolic rate. As suggested by one study using apoE-deficient mice, apoE is required for the cellular uptake of apoB-containing lipoproteins by SR-BI (23). In contrast, hepatic SR-BI overexpression in fibrate-treated apoE knockout mice decreased plasma apoB levels significantly by more than 40% and reversed fibrate-induced hypercholesterolemia (24). To our knowledge, this is the first report implicating SR-BI in hepatic VLDL production. However, circumstantial evidence has been provided by previous studies.

In the important first demonstration that SR-BI increases the catabolic rate of HDL and enhances cholesterol uptake in vivo in mice, FPLC profiles indicated that, after a lag phase, on days 7, 10, and 14 following injection of AdSR-BI, levels of apoB-containing lipoproteins increased substantially (7). This observation would argue against a sole effect of SR-BI on the catabolism of apoB-containing lipoproteins. Therefore, we directly measured hepatic VLDL production rates in SR-BI knockout as well as SR-BI overexpressing mice and found these to be positively related to the SR-BI expression level. In the previous study, hepatic LDLR mRNA expression was reported to be unchanged in response to SR-BI overexpression (7). This is in contrast to our results that SREBP2 as well as its target gene LDLR are significantly decreased following injection of AdSR-BI, in line with increased hepatic cholesterol content.

Interestingly, hepatic VLDL production rates in the context of altered hepatic SR-BI expression were measured in only one other earlier study using SR-BI knockout mice (6). This report revealed a clear trend toward a 30% decrease in VLDL-TG production in SR-BI knockout mice (6) that, however, did not reach statistical significance. These studies used tyloxapol as a means of blocking Anacetrapib endogenous VLDL catabolism, whereas we employed P-407 in our present study.