The high density lipoprotein (HDL) receptor SR-BI (scavenger receptor class B type I) mediates the selective uptake of plasma HDL cholesterol by the liver and steroidogenic tissues. As a consequence, SR-BI can inf luence plasma HDL cholesterol levels, HDL structure, biliary cholesterol concentrations, and the uptake, storage, and utilization of cholesterol by steroid hormone-producing cells. Here we used homozygous null SR-BI knockout mice to show that SR-BI is required for maintaining normal biliary cholesterol levels, oocyte development, and female fertility. We also used SR-BI͞apolipoprotein E double homozygous knockout mice to show that SR-BI can protect against early-onset atherosclerosis. Although the mechanisms underlying the effects of SR-BI loss on reproduction and atherosclerosis have not been established, potential causes include changes in (i) plasma lipoprotein levels and͞or structure, (ii) cholesterol f lux into or out of peripheral tissues (ovary, aortic wall), and (iii) reverse cholesterol transport, as indicated by the significant reduction of gallbladder bile cholesterol levels in SR-BI and SR-BI͞apolipoprotein E double knockout mice relative to controls. If SR-BI has similar activities in humans, it may become an attractive target for therapeutic intervention in a variety of diseases.High density lipoprotein (HDL)-cholesterol levels are inversely proportional to the risk for atherosclerosis (1). This may be due partly to ''reverse cholesterol transport'' (RCT), in which HDL is proposed to remove excess cholesterol from cells, including those in the artery wall (2-7), and transport it, either indirectly or directly (8, 9), to the liver for biliary secretion. HDL also can deliver cholesterol directly to steroidogenic tissues (adrenal gland, testis, ovary) for storage in cytoplasmic cholesteryl ester droplets and for steroid hormone synthesis (10-12). Thus, HDL may influence a variety of endocrine functions, including reproduction. A key mechanism of receptor-mediated direct delivery of HDL cholesteryl esters to the liver and steroidogenic tissues is selective cholesterol uptake, in which only the cholesteryl esters of the HDL particles (not the apolipoproteins) are transferred efficiently to cells (8, 9).The class B type I scavenger receptor, SR-BI, is a cellsurface HDL receptor that mediates selective lipid uptake (13-21; reviewed in refs. 22 and 23). It is most highly expressed in the liver and steroidogenic tissues, in which its activity is regulated by trophic hormones (13, 24-31). As a consequence, SR-BI is a key regulator of HDL cholesterol levels (17-21) and adrenal cholesterol stores (18). The finding that hepatic SR-BI overexpression leads to significant increases in biliary cholesterol content (17, 32) is consistent with gene-targeting studies (18,19) that suggest an important role for SR-BI in RCT. In addition to HDL, SR-BI can bind other ligands, including lipoproteins [LDL, modified LDL, very low density lipoprotein (VLDL)] and apolipoproteins (33-37), and can mediate efflux...

Because cholesterol is a precursor for the synthesis of steroid hormones, steroidogenic tissues have evolved multiple pathways to ensure adequate supplies of cholesterol. These include synthesis, storage as cholesteryl esters, and import from lipoproteins. In addition to endocytosis via members of the low-density lipoprotein receptor superfamily, steroidogenic cells acquire cholesterol from lipoproteins by selective lipid uptake. This pathway, which does not involve lysosomal degradation of the lipoprotein, is mediated by the scavenger receptor class B type I (SR-BI). SR-BI is highly expressed in steroidogenic cells, where its expression is regulated by various trophic hormones, as well as in the liver. Studies of genetically manipulated strains of mice have established that SR-BI plays a key role in regulating lipoprotein metabolism and cholesterol transport to steroidogenic tissues and to the liver for biliary secretion. In addition, analysis of SR-BI-deficient mice has shown that SR-BI expression is important for alpha-tocopherol and nitric oxide metabolism, as well as normal red blood cell maturation and female fertility. These mouse models have also revealed that SR-BI can protect against atherosclerosis. If SR-BI plays similar physiological and pathophysiological roles in humans, it may be an attractive target for therapeutic intervention in cardiovascular and reproductive diseases.

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar͞vesicular and stacked discoidal particles reminiscent of those in lecithin͞cholesterol acyltransferase deficiency and cholestasis). Treatment with the lipid-lowering, antiatherosclerosis, and antioxidation drug probucol extended life to as long as 60 weeks (mean 36 weeks), and at 5-6 weeks of age, virtually completely reversed the cardiac and most RBC pathologies and corrected the unesterified to total cholesterol ratio (0.3) and associated distinctive abnormal lipoprotein morphologies. Manipulation of the timing of administration and withdrawal of probucol could control the onset of death and suggested that critical pathological changes usually occurred in untreated double knockout mice between Ϸ3 (weaning) and 5 weeks of age and that probucol delayed heart failure even after development of substantial CHD. The ability of probucol treatment to modulate pathophysiology in the double knockout mice enhances the potential of this murine system for analysis of the pathophysiology of CHD and preclinical testing of new approaches for the prevention and treatment of cardiovascular disease.atherosclerosis ͉ heart failure ͉ myocardial infarction ͉ unesterified cholesterol C oronary artery atherosclerosis is a major cause of myocardial infarction (MI) and death. We have described a murine model of human coronary heart disease (CHD) (1) that is based on targeted homozygous null mutations in two genes whose products play important roles in normal lipoprotein metabolism and protect mice from atherosclerosis: the high-density lipoprotein (HDL) receptor SR-BI (scavenger receptor class B, type I) (2, 3) and the lipoprotein component apolipoprotein E (apoE) (4-7).Low-fat chow-fed, homozygous null, apoE knockout (KO) mice are hypercholesterolemic (4, 5), develop atherosclerosis between 3 and 4 months of age, and usually live a long life (Ͼ1 year), although older animals can sometimes develop coronary artery occlusions and apparently associated pathology (8, 9). SR-BI controls HDL structure and metabolism and appears to be important for ''reverse cholesterol transport,'' HDL-mediated transport of cholesterol from peripheral tissues (including atherosclerotic plaques) to the liver and then to the bile for excretion (2, 3, 10-16). SR-BI delivers cholesteryl esters and other lipids from HDL to cells via selective lipid uptake (2, 3, 10, 17, 18) and can also mediate un...

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We determined the common polymorphism of apolipoprotein E (E2, E3, and E4), apolipoprotein B Xba I polymorphism, and apolipoprotein C-III Sst I polymorphism in almost all Finnish centenarians alive in 1991 (n=179/185). Plasma lipid and lipoprotein levels in different apolipoprotein genotypes were also measured. In comparison with younger Finnish populations studied previously, the frequency of the apolipoprotein E e2 allele was almost twice as high (7.0% versus 4.1%; P<.05) and that of the e4 allele only approximately one third as high (8.4% versus 22.7%; P<.001) in the centenarians. Plasma cholesterol and high-density lipoprotein cholesterol levels tended to be lowest in the group with the e2 allele (4.33 mmol/L and 1.41 mmol/L, respectively), intermediate in those with the e3 allele (4.57 mmol/L and 1.48 mmol/L, respectively), and highest in those with the E4 allele (4.82 mmol/L and 1.60 mmol/L, respectively). The frequencies of the apolipoprotein B XI and X2 alleles (Xba I restriction A polipoproteins occupy a central position in lipo-/ \ protein metabolism. Apolipoprotein E (apoE) A. \ _ is present in chylomicrons and very-low-density lipoprotein and their lipolytic degradation products, ie, chylomicron remnants and intermediate-density lipoproteins. -2 It also plays a role in cholesterol absorption and in the receptor-mediated uptake of lipoprotein particles by the liver. Apolipoprotein B (apoB) is essential for the synthesis and secretion of chylomicrons in the intestine and of VLDL in the liver and serves as the ligand allowing the low-density lipoprotein (LDL) receptor to recognize LDL.1 ' 2 Apolipoprotein C-III (ApoC-III) is a major protein constituent of triglyceride-rich lipoproteins and may also affect the activities of lipoprotein and hepatic Upases. Common genetic polymorphisms of apoE, apoB, and apoC-III have been found to influence serum lipid levels in several populations (for reviews, see References 2 through 6). Three major apoE isoforms (E2, E3, and E4), encoded by three separate alleles (E2, E3, and e4), in different combinations determine six different phenotypes. 57 Several studies have indicated that the e4

SummaryThe point mutation Arg506->Gln of factor V was recently shown to be an important and relatively common genetic cause of venous thromboembolism. Using a DNA technique based on polymerase chain reaction, we surveyed the blood samples of 236 patients with ischaemic stroke or a transient ischaemic attack, 122 survivors of myocardial infarction and 137 control subjects for the presence of this mutation. Although the frequency of the factor V mutation in patients with arterial disease (4.5%) was not significantly different from that in healthy blood donors (2.9%), a carrier status for this mutant gene was associated with symptoms of migraine and relatively mild angiographic abnormalities among patients with cerebrovascular disease. A more extensive study addressing the occurrence and significance of the mutant factor V mutation in patients with vasospastic cerebrovascular diseases seems to be warranted.

Baseline clinical and BP parameters may be used to predict the efficacy of antihypertensive therapies. The GENRES Study material should provide an excellent platform for future pharmacogenetic analyses of antihypertensive drug responsiveness.

No association between Alzheimer's disease (AD) and apolipoprotein E type epsilon 4 (ApoE epsilon 4) phenotype was found among centenarians in Finland (N = 179). The data are based on ascertainment of all centenarians in Finland in 1991. All examinations were conducted during 1991. The diagnoses of dementia and AD were based on clinical grounds, conforming to DSM-III-R and NINCDS-ADRDA criteria. The percentage of ApoE epsilon 4 alleles among the centenarians was 8.7% (31 of 358 alleles). This is significantly lower than percentages found in younger Finnish populations. Thirty (16.8%) of the 179 centenarians were epsilon 4 allele carriers. One hundred fifty-one (84.4%) of the centenarians were women. Twenty-eight (18.5%) of the women had at least one epsilon 4 allele, as did two (7.1%) of the men. The prevalence of clinically diagnosed AD was 26.8%; 44% of the subjects were cognitively normal, 23% had signs of cognitive decline or at most mild dementia (with no differential diagnosis), and 6% had a dementia clinically diagnosed as being due to some cause other than AD. For AD cases versus cognitively normal subjects, the odds ratio associated with being a carrier of the epsilon 4 allele was 1.34 (p = 0.64; 95% CI = [0.5, 3.3]). Among women, the odds ratio was 0.99 (p = 1.0; 95% CI = [0.4, 2.6]). There were fewer, but not significantly so, epsilon 4 carriers among subjects with cognitive decline or at most mild dementia (12.2%) than there were among the cognitively normal subjects (16.5%). The AD patients had no evidence of difficulty standing on a flat stationary surface unless the surface suddenly moved.(ABSTRACT TRUNCATED AT 250 WORDS)