The risk of atherosclerosis, a leading cause of cardiovascular disease and death, is inversely related to plasma levels of high-density lipoprotein (HDL) cholesterol, although the mechanism of this protective effect is unclear. The class B scavenger receptor, SR-BI, is the first HDL receptor to be well defined at a molecular level and is a mediator of selective cholesterol uptake in vitro. It is expressed most abundantly in steroidogenic tissues, where it is coordinately regulated with steroidogenesis by adrenocorticotropic hormone (ACTH), human chorionic gonadotropin (hCG) and oestrogen, and in the liver, where its expression in rats is suppressed by oestrogen. Here we show that adenovirus-mediated, hepatic overexpression of SR-BI in mice on both sinusoidal and canalicular surfaces of hepatocytes results in the virtual disappearance of plasma HDL and a substantial increase in biliary cholesterol. SR-BI may directly mediate these effects by increasing hepatic HDL cholesterol uptake or by increasing cholesterol secretion into bile, or both. These results indicate that SR-BI may be important in hepatic HDL metabolism, in determining plasma HDL concentrations, and in controlling cholesterol concentrations in bile, and thus may influence the development and progression of atherosclerosis and gallstone disease.

Background There is no angiographically demonstrable obstructive coronary artery disease (CAD) in a significant minority of patients with myocardial infarction (MI), particularly women. We sought to determine mechanism(s) of MI in this setting using multiple imaging techniques. Methods and Results Women with MI were enrolled prospectively, prior to angiography if possible. Women with ≥50% angiographic stenosis or use of vasospastic agents were excluded. Intravascular ultrasound (IVUS) was performed during angiography and cardiac magnetic resonance imaging (CMR) within one week. Fifty women (age 57±13 years) had median peak troponin 1.60 ng/ml; 11 had ST elevation. Median diameter stenosis of the worst lesion was 20% by angiography; 15 patients (30%) had normal angiograms. Plaque disruption was observed in 16/42 patients (38%) undergoing IVUS. There were abnormal myocardial CMR findings in 26/44 patients (59%) undergoing CMR: late gadolinium enhancement (LGE) in 17 and T2 signal hyperintensity indicating edema in 9 additional patients. The most common LGE pattern was ischemic (transmural/subendocardial). Non-ischemic LGE patterns (midmyocardial/subepicardial) were also observed. LGE was infrequent with plaque disruption but T2 signal hyperintensity was common with plaque disruption. Conclusions Plaque rupture and ulceration are common in women with MI without angiographically demonstrable obstructive CAD. LGE is also common in this cohort of women, with an ischemic pattern of injury most evident. Vasospasm and embolism are possible mechanisms of ischemic LGE without plaque disruption. IVUS and CMR provide complementary mechanistic insights in female MI patients without obstructive CAD and may be useful in identifying potential etiologies and therapies.

The class B, type I scavenger receptor, SR-BI, binds high density lipoprotein (HDL) and can mediate selective uptake of HDL cholesteryl esters by cultured cells. The high levels of expression of SR-BI in steroidogenic tissues and the importance of selective uptake from HDL as a source of cholesterol for steroidogenesis raised the possibility that SR-BI may participate in cholesterol delivery to steroidogenic tissues in vivo. We have used immunoblotting and immunohistochemical methods to show that SR-BI is specifically expressed in a distinctive pattern on the surfaces of steroid-producing cells in the murine adrenal gland's cortex and that its expression in vivo is induced by adrenocorticotropic hormone and suppressed by glucocorticoids. Thus, expression of SR-BI protein is coordinately regulated with adrenal steroidogenesis. These data provide strong support for the hypothesis that SR-BI is a physiologically relevant HDL receptor that provides substrate cholesterol for steroid hormone synthesis.The intercellular transport of lipids, including cholesteryl esters and triglycerides, through the blood involves their packaging into water-soluble lipoproteins and the targeted delivery of lipoprotein lipids to cells via receptor-mediated processes (1). The best understood of the lipoprotein transport systems is the LDL 1 receptor pathway of receptor-mediated endocytosis. LDL binds to its surface receptor, is internalized via coated pits, and the entire lipoprotein particle is subsequently degraded in lysosomes to release free cholesterol to the cell. HDL also delivers cholesterol to cells through a less well defined process called selective cholesterol uptake (2-12). HDL particles bind to surface receptors on target cells, their cholesteryl esters are selectively transferred into the cells without the degradation of the lipoprotein particle, and the lipid-depleted particles including their two major apolipoproteins, apoA-I and apoA-II, are released from the cells, a process that is fundamentally different from the endocytic uptake of lipoproteins mediated by members of the LDL receptor family.The HDL-cholesteryl ester selective uptake pathway occurs in cultured hepatocytes and in the liver (3, 4, 7-9, 11, 12), where it may contribute to the clearance of plasma cholesteryl ester in the terminal stage of reverse cholesterol transport (13,14). The HDL selective uptake pathway plays a prominent role in cholesterol delivery to steroidogenic cells of mice and rats where it appears to be responsible for the overwhelming majority of the uptake of HDL cholesterol (3,4,6,8,12). Indeed, HDL is significantly more effective than LDL in supplying cholesterol for cholesteryl ester accumulation and corticosterone production in adrenal glands of rats and mice (5,(15)(16)(17). Using gene knockout mice, Plump et al. (18) showed that apoA-I deficiency caused an almost complete failure to accumulate cholesteryl ester in steroidogenic cells of the adrenal gland, ovary, and testis, a result illustrating the importance of HDL-apoA-I, presum...