In general, the effect of SR-BI on VLDL production should not be regarded as an exclusive denominator of steady-state plasma VLDL cholesterol levels as these depend on factors influencing the production rate as well as the catabolic rate. However, as we observed significant and congruent results on SR-BI facilitating OSI-744 hepatic VLDL production, both in the knockout mouse and in a dose-dependent fashion under conditions of hepatic SR-BI overexpression, we believe that this property of SR-BI has physiological relevance. Although in chow-fed SR-BI transgenic mice with life-long metabolic adaptations, plasma levels of cholesterol within apoB-containing lipoproteins are lower, indicating the catabolism effect of SR-BI overweighing the effect on production rate (25�C27), altering the metabolic context in SR-BI transgenic models reveals effects of SR-BI overexpression that are consistent with increased production of apoB-containing lipoproteins.

Feeding a Western-type diet to SR-BI transgenic mice was associated with increased plasma levels of apoB-containing lipoproteins (25, 27). In addition, SR-BI transgenic mice on the human apoB-transgenic background fed an atherogenic diet also displayed increased levels of apoB-containing lipoproteins, which, interestingly, translated in this model into increased atherogenesis (28). Other available studies in the literature that achieved SR-BI overexpression using a recombinant adenovirus all investigated earlier time points, namely day 3 or day 5 after adenovirus injection, and observed on these days very similar steady-state plasma lipoprotein effects as seen in our present report (4, 21, 29, 30), mostly no or minor effects on VLDL cholesterol.

The only other study looking at time points later than day 5, however, revealed plasma lipid and lipoprotein data similar to our study, namely increased apoB-containing lipoproteins on day 7 and later (7). Of note, however, none of the previous studies discussed in this paragraph measured hepatic VLDL production rates. Gene expression analysis in SR-BI knockout as well as in SR-BI overexpressing mice demonstrated that the SR-BI expression level is inversely related to the expression of SREBP2 and its target genes LDLR and HMG-CoA reductase. These results are in agreement with previous in Drug_discovery vitro findings that SR-BI delivers HDL cholesterol to an intracellular regulatory pool (31). Because SREBP2 has been established as a sensitive sensor for the ER cholesterol content (32), these results indicate that SR-BI-mediated cholesterol uptake results in increased ER cholesterol content, whereas the absence of SR-BI leads to a depletion in ER cholesterol.