Recent studies have indicated that the scavenger receptor class B type I (SR-BI) may play an important role in the uptake of high density lipoprotein (HDL) cholesteryl ester in liver and steroidogenic tissues. To investigate the in vivo effects of liver-specific SR-BI overexpression on lipid metabolism, we created several lines of SR-BI transgenic mice with an SR-BI genomic construct where the SR-BI promoter region had been replaced by the apolipoprotein (apo)A-I promoter. The effect of constitutively increased SR-BI expression on plasma HDL and non-HDL lipoproteins and apolipoproteins was characterized. There was an inverse correlation between SR-BI expression and apoA-I and HDL cholesterol levels in transgenic mice fed either mouse chow or a diet high in fat and cholesterol. An unexpected finding in the SR-BI transgenic mice was the dramatic impact of the SR-BI transgene on non-HDL cholesterol and apoB whose levels were also inversely correlated with SR-BI expression. Consistent with the decrease in plasma HDL and non-HDL cholesterol was an accelerated clearance of HDL, non-HDL, and their major associated apolipoproteins in the transgenics compared with control animals. These in vivo studies of the effect of SR-BI overexpression on plasma lipoproteins support the previously proposed hypothesis that SR-BI accelerates the metabolism of HDL and also highlight the capacity of this receptor to participate in the metabolism of non-HDL lipoproteins.The risk of developing coronary artery disease is directly related to plasma levels of low density lipoprotein (LDL) 1 cholesterol and inversely associated with the concentration of high density lipoprotein cholesterol (HDL) (1, 2). Although numerous studies have revealed many steps involved in LDL metabolism, significantly less is known about HDL metabolism. Novel insights concerning the metabolism of HDL have come from a recent series of experiments suggesting that the scavenger receptor class B type I (SR-BI) is an HDL receptor (3-9). SR-BI, a member of the CD36 superfamily, was originally cloned as a receptor for modified LDL (10 -12). Transfected cells expressing SR-BI show high affinity binding with HDL and take up cholesteryl ester from the particle by a selective uptake pathway markedly distinct from the LDL receptor pathway. Further support for SR-BI being an HDL receptor comes from the observations that SR-BI is expressed in liver and non-placental steroidogenic tissues, long hypothesized sites of HDL cholesterol delivery (3-6).The expression of SR-BI in tissues appears to be responsive to changes in hormonal status and HDL cholesteryl ester supply (13-16). In the adrenal glands of knockout mice deficient in apoA-I (13), hepatic lipase (13), or lecithin-cholesterol acyltransferase (14), the expression of SR-BI is increased markedly. Moreover, the expression of SR-BI is up-regulated in the adrenal gland and down-regulated in the liver of rats after high dose estrogen treatment (15). The estrogen-induced increase of SR-BI is accompanied by enhanced uptake of lipid ...