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Departments of Molecular Genetics (G.C., H.S., H.H.H.), Internal Medicine (L.Z., K.L.P., T.H., H.H.H.), and Pathology (J.A.R.) University of Texas Southwestern Medical Center at Dallas Dallas, Texas 75235
The scavenger receptor, class B, type I (SR-BI), is the predominant receptor that supplies plasma cholesterol to steroidogenic tissues in rodents. We showed previously that steroidogenic factor-1 (SF-1) binds a sequence in the human SR-BI promoter whose integrity is required for high-level SR-BI expression in cultured adrenocortical tumor cells. We now provide in vivo evidence that SF-1 regulates SR-BI. During mouse embryogenesis, SR-BI mRNA was initially expressed in the genital ridge of both sexes and persisted in the developing testes but not ovary. This sexually dimorphic expression profile of SR-BI expression in the gonads mirrors that of SF-1. No SR-BI mRNA was detected in the gonadal ridge of day 11.5 SF-1 knockout embryos. Both SR-BI and SF-1 mRNA were expressed in the cortical cells of the nascent adrenal glands. These studies directly support SF-1 participating in the regulation of SR-BI in vivo. We examined the effect of cAMP on SR-BI mRNA and protein in mouse adrenocortical (Y1-BS1) and testicular carcinoma Leydig (MA-10) cells. The time courses of induction were strikingly similar to those described for other cAMP- and SF-1-regulated genes. Addition of lipoproteins reduced SR-BI expression in Y1-BS1 cells, an effect that was reversed by administration of cAMP analogs. SR-BI mRNA and protein were expressed at high levels in the adrenal glands of knockout mice lacking the steroidogenic acute regulatory protein; these mice have extensive lipid deposits in the adrenocortical cells and high circulating levels of ACTH. Taken together, these studies suggest that trophic hormones can override the suppressive effect of cholesterol on SR-BI expression, thus ensuring that steroidogenesis is maintained during stress. . Both low-density lipoproteins (LDL) and high-density lipoproteins (HDL) can deliver cholesterol to support steroidogenesis, with the relative contributions of these two lipoproteins differing among species.
More than 20 yr ago, HDL was found to be the major source of cholesterol for steroidogenesis in rodents (4–6). The dominant role of HDL in maintaining cholesterol ester stores in steroidogenic tissues is reflected by the marked lipid depletion seen in the adrenocortical cells of mice lacking apolipoprotein AI, the major apolipoprotein of HDL (7). The adrenal cortical cells of rats made hypolipidemic by treatment with either high-dose estrogen or 4-aminopyrazolopyrimidine are also lipid depleted (5, 8, 9).
Cholesterol delivery to steroidogenic tissues from HDL differs from the well characterized LDL receptor pathway (5, 6). The cholesterol uptake from HDL is selective; lipids are transported into the cell without the concomitant uptake and degradation of the apolipoproteins (10). In contrast, after LDL binds to its cell surface receptor, the entire particle is taken up by receptor-mediated endocytosis and delivered to lysosomes, where the apoproteins are degraded and the cholesterol esters are enzymatically hydrolyzed to release cholesterol (11).
The protein that mediates the selective uptake of lipids from HDL was identified 3 yr ago by Krieger and colleagues (12) and named scavenger receptor, class B, type I (SR-BI) (12). SR-BI is expressed at highest levels in those tissues and cell types most active in selective uptake in vivo: the liver, the zona fasciculata and zona reticularis of the adrenal glands, the theca cells and corpus luteum of the ovaries, and the Leydig cells of the testes (12–16). Antibodies to the extracellular domain of SR-BI block HDL-cholesterol ester uptake and HDL-stimulated synthesis of steroids in cultured mouse adrenocortical cells (17). This finding is consistent with SR-BI playing a major role in supplying steroidogenic cells with cholesterol. Furthermore, SR-BI knockout mice have lipid-depleted adrenal glands and a 2- to 3-fold increase in plasma levels of HDL-cholesterol (18). Mice with a reduced amount of SR-BI showed decreased selective uptake of cholesterol esters (19).
Trophic hormones, acting by a cAMP-dependent protein kinase pathway (20), induce the expression of both the LDL receptor and SR-BI (9, 13, 21, 22). Trophic hormones fail to increase LDL receptor activity in adrenocortical cells when steroidogenesis is inhibited and the intracellular cholesterol content is maintained by the addition of exogenous lipoproteins (9). These observations are consistent with the model in which trophic hormones deplete intracellular cholesterol stores by stimulating steroidogenesis and thereby indirectly increase LDL receptor activity (23).
The mechanism by which trophic hormones up-regulate SR-BI expression is not known. SR-BI levels are elevated in the adrenal glands of multiple strains of genetically manipulated mice that are hypolipidemic, including some apoAI-/- mice (24) and mice in which the lecithin-cholesterol acyl transferase or the hepatic lipase genes have been inactivated (24, 25). These observations suggest that the levels of SR-BI, like the LDL receptor, may be regulated by the intracellular content of cholesterol.
cAMP acts synergistically with the nuclear hormone receptor steroidogenic factor 1 (SF-1) to activate the genes encoding multiple components of the steroidogenic pathway (26). All cytochrome P450 steroid hydroxylases and the steroidogenic acute regulatory protein (StAR), which mediates transport of cholesterol from the cytoplasm to the inner mitochondrial membrane, are regulated by SF-1 via SF-1-responsive promoter elements (27, 28). The human CLA-1/SR-BI gene also contains a consensus SF-1 binding motif in its promoter region (29). We previously showed that SF-1 binds to this site in a sequence-dependent manner and that this element is required for high-level expression of SR-BI promoter constructs in cultured adrenocortical cells (29).
In this paper, we explore the regulation of SR-BI mRNA expression in steroidogenic tissues of the mouse and examine the relative roles of trophic hormones (via cAMP and SF-1) and the intracellular concentration of cholesterol in regulating the levels of SR-BI in cultured mouse Yl adrenocortical cells.
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