Oxygenated derivatives of cholesterol (oxysterols) exist in the human body as intermediates in the biosynthetic pathways of bile acids, steroid hormone and vitamin D. 7α-Hydroxycholesterol and 27-hydroxycholesterol are identified as intermediates in the conversion of cholesterol to bile acids in the liver. Steroid hormones are formed from cholesterol via pregnenolone through a series of sequential hydroxylations at carbon-22 (C-22) and C-20. The first step in the biosynthesis of vitamin D occurs in the skin and uses 7-dehydrocholesterol. The enzymatic production of 24-hydroxycholesterol was demonstrated in the developing brain. In addition to these specific enzymatic reactions, nonspecific peroxidation in vivo and non-enzymatic autoxidation of cholesterol may occur, because of the susceptibility of cholesterol to the attack by oxygen molecules. In the 1970's, Kandutsch and colleagues demonstrated that oxysterols were potent inhibitors of HMG-CoA reductase activity. Many oxysterols such as 7-ketocholesterol and 25-hydroxycholesterol may play a role as the intracellular regulator of cholesterol synthesis. Oxysterols repress enzymes of sterol biosynthesis (HMG-CoA reductase and HMG-CoA synthase), and activate enzymes of catabolism (7α-hydroxycholesterol) and sterol storage (acyl CoA: cholesterol acyltransferase). These actions prevent the accumulation of unesterified cholesterol within cells. However, the molecular mechanism(s) of action of oxysterols are not well understood in all instances. The similarity in the actions by LDL-cholesterol and oxysterols bring a hypothesis that the action of LDL-cholesterol may be mediated by oxysterols in the cell. Then, oxysterols have been demonstrated to possess a variety of biological properties, including cytotoxicity, atherogenicity, mutagenicity and carcinogenicity. In this paper, recent studies on oxysterols, especially monooxygenated cholesterol derivatives, were reviewed with regard to the analysis, biological significance and specific diseases which are closely related with metabolic disorders of oxysterols including atherosclerosis and cerebrotendinous xanthomatosis and so on.

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Increasing reliability, validity and biological consistency of B-mode ultrasonography for quantifying carotid atherosclerosis provide rationale for its application to evaluate lipid lowering therapy by pravastatin. The results are in favor for the treatment on the slowing atherosclerotic progression.
Quantitative angiography is also successfully applied to determine the progressive alterations of coronary atherosclerosis in spite of some limitations. Several controlled double blind studies indicated that the rate of atherosclerosis progression could be reduced based on changes in luminal dimension.
Angioscopy, intravascular ultrasonography and laser-induced fluorescence analysis are still in the investigational stage for quantifying practically the atherosclerotic lesions.

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When endogenous synthesis of cholesterol is blocked by an HMG-CoA reductase inhibitor (pravastatin), proliferation of phytohemagglutinin (PHA)-stimulated human lymphocytes is markedly inhibited unless an exogenous source ofcholesterol is supplied. Based on this principle, we simplified and modified the method of Lipsky et al. to assay functional LDL receptors. Using our method, we examined the capacity of HDL_2b and LDL to supply cholesterol to lymphocytes from FH heterozygotes or normal subjects. Peripheral blood lymphocytes were isolated from the venous blood of 5 patients with heterozygous FH and 10 healthy adults. LDL and HDL_2b were isolated by ultracentrifugation from the serum of normal fasting adults, and the HDL_2b fraction that contained Apo E but not Apo B was prepared by a heparin-Sepharose column. The ability of HDL_2b cholesterol to reverse pravastatinmediated inhibition of lymphocyte proliferation in FH heterozygotes was concentration-dependent. However, the effect of HDL_2b was weaker than that of LDL. In addition, HDL_2b provided less cholesterol to lymphocytes in FH heterozygotes than in normal subjects. These findings suggested that provision of cholesterol from not only LDL but also HDL_2b was depressed by dysfunction of LDL receptor in FH heterozygotes.

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The tortuosity of the abdominal aorta is generally believed to be associated with atherosclerosis.
We developed an index of tortuosity, “elongation ratio: E (%)”, which is based on two lengths: the calculated length of the abdominal aorta if it were not tortuous between the renal artery and the common iliac bifurcation (L1), and the actual length of the abdominal aorta between those two points (L2). E(%) was calculated as L2-L1/L1×100 to study the relationship between aortic tortuosity and atherosclerosis. We compared E (%) to Balcon's coronary index, the severity of stenosis in the abdominal aorta and pulse wave velocity (PWV_C). We used angiograms to measure E (%) in 123 patients suspected of ischemic heart disease.
E (%) was not correlated either with Balocon's coronary index or with the severity of stenosis in the abdominal aorta in any of the four age ranges studied (40∼49, 50∼59, 60∼69, 70 and over). However, E (%) was positively correlated with age, and also positively correlated with PWV_C in patients who were older than 70 years of age.
Our study indicated that aging accelerates the tortuosity of the abdminal aorta.

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The aim of this study is to investigate the effects of pravastatin on hypercholesterolemia in the 32 hospitals of Kochi Prefecture. In this study 277 (73 men, 204 women) were recruited from 32 hospitals, who showed more than 220mg/dl of serum total cholesterol (TC).
They were administered with pravastatin (Mevalotin®) 10mg once daily after either breakfast or supper for 36 months. Fasting blood samples were drawn early in the morning for measuring biochemical parameters. Serum TC and LDL cholesterol (LDL-C) one month after pravastatin administration decreased significantly from 270mg/dl to 220mg/dl and from 182mg/dl to 135mg/dl, respectively. The changes maintained steady states until 36 months.
The same grade of decrements in TC and LDL-C were found in 133 patients with essential hypertension, 46 patients with ischemic heart disease and 45 diabetic patients. Serum triglyceride (TG) decreased significantly from 189mg/dl to 160mg/dl one month after its administration and maintained a steady state until 36 months. Serum HDL cholesterol (HDL-C) increased significantly from 50.9mg/dl to 53mg/dl one month after its administration.
Atherogenic index of (TC—HDL-C)/HDL-C ratio decreased significantly from 4.8 to 3.5 one month after and maintained a steady state. Apolipoprotein B decreased significantly from 131mg/dl to 105mg/dl.
The lowering-rates of TC, LDL-C, TG and HDL-C were 18.4%, 25.4%, 6.7% and 8%, respectively. There were significantly reverse correlations between the prevalues and the differences (postvaluesprevalues) of serum lipids 3 months after: -0.511 in TC, -0.49 in LDL-C, -0.6 in TG and -0.277 in HDL-C, respectively. Serum lipids tended to be lower when the prevalues were higher. Regression line of HDL-C was the following equation: y=12.11-0.1893x, showing 62mg/dl as the critical value and the bidirectional change of HDL-C. By administration of pravastatin hyperlipidemia was improved in 89.2% with slightly adverse effects of 1.4%, the safety was 94.6% and the availability was 92.1%.
From the above findings pravastatin administration was effective on lipid-lowering and tolerated in patients with hypercholesterolemia.
*38 medical physicians of 32 hospitals in Kochi prefecture, Japan

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This study was designed to determine whether pravastatin is effective on lipid-lowering in elderly patients with hypercholesterolemia. There were recruited in this study 155 patients as an adult group aged less than 64 years and 122 patients as an elderly group aged more than 65 years. Fasting blood samples were drawn early in the morning for measuring biochemical parameters. They received pravastatin (Mevalotin®) 10mg once daily after either breakfast or supper.
Serum total cholesterol (TC) decreased from 270mg/dl to 225mg/dl one month after pravastatin administration in the adult group, and from 270mg/dl to 220mg/dl in the elderly group. Serum LDL cholesterol (LDL-C) decreased from 180mg/dl to 140mg/dl one month after in both groups. Serum triglyceride (TG) decreased from 280mg/dl to 180mg/dl 30 months after in the adult group and from 160mg/dl to 140mg/dl in the elderly group. Serum HDL cholesterol (HDL-C) increased slightly one month after in the adult group and increased in the elderly group. Serum TC and LDL-C had the lowering-rate of 17.4% and 21.8% respectively in the adult group, and 19.5% and 30% in the elderly group.
In comparison between the prevalues and the differences (postvalues-prevalues), there were found significant reverse correlations in serum lipids one month after its administration. The correlation coefficients were calculated in both adult and elderly groups respectively: -0.705 and -0.208 in TC, -0.652 and -0.395 in LDL-C, -0.787 and -0.393 in TG, and -0.348 and -0.59 in HDL-C. The regression lines of HDL-C were expressed: y=16.96-0.2736x in the adult group and y=17.36-0.305x in the elderly group, showing 62mg/dl and 56.9mg/dl as the critical value, respectively. According to the results, there are bidirectional changes of serum HDL-C after its administration.
From the above findings the effects of pravastatin on TC and LDL-C were almost same between the adult patients and elderly patients.
*38 medical physicians of 32 hospitals in Kochi prefecture, Japan

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The lipoprotein components of RLP were studied in 54 subjects, whose RLP-cholesterol (C) levels were abnormally high (over 20 mg/dl), using a combination of an improved HPLC method and an immunoabsorption method (immunoaffinity mixed gels coupled with anti human apo A-I and apo B-100 monoclonal antibodies). Normolipidemic and type IIa subjects showed RLP-C levels lower than 20 mg/dl. The RLP-C levels in 18 normolipidemic control subjects were 3.8±1.3 mg/dl (mean±S.D.), indicating that over 98% of the LDL and HDL bound to the immunoafl'inity gels.
The serum RLP-C levels and the lipoprotein components in RLP showed almost no differences among the different lots of the immunoaffinity gels.
The major components of RLP were shown to be lipoproteins of chylomicron (CM) and VLDL size in type I and V. Lipoproteins of VLDL size were major components in type IIb and IV. RLP in type III was cholesterol-rich and smaller in particle size than that of other types of hyperlipoproteinemia.
In hypertriglyceridemia over 250 mg/dl, lipoproteins of CM and VLDL size were shown to be the major components of RLP, which indicated the delayed clearance of larger triglyceride-rich lipoproteins. The RLP-C levels reflect the concentrations of the lipoproteins of CM and VLDL size as an independent marker for lipid testing such as HDL and total cholesterol. Therefore, the determination of serum RLP-C levels and a detailed analysis by HPLC seem to be a useful clinical marker for the detection of abnormal lipid metabolism in hyperlipoproteinemia.

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The role of Lp (a) in platelet activities, coagulation and fibrinolysis was examined. 1) A control group study: Ninety nine control subjects were selected from individuals who had had an annual health check up during the period of this study. Lp (a) showed a skewed distribution toward higher values. The median and mean concentration±SD of Lp(a) were 14.4mg/dl and 24.0±21.7mg/dl. 2) A cross-sectional study on 24 patients with myocardial infarction (CHD) and 28 with cerebral infarction (CVD). The Lp (a) value in the CHD and CVD groups was higher (median and mean±SD); in CHD (26.9 30.1±20.9mg/dl) and in CVD (30.1, 31.0±20.1mg/dl) than in the controls (14.0, 24.0±21.7mg/dl). The mean total cholesterol, triglycerides and HDL-cholesterol concentrations were all in the normal range, except for HDL-c in CHD. The Lp (a) concentration was not correlated with that of the serum lipids. The concentration of platelet releasing substance of plasma β-thromboglobulin (β-TG) was 39±25ng/ml in the control, but 51±33ng/ml in CHD and 51±32ng/ml in CVD. The plasma platelet. factor-4 (PF-4) concentrations showed the same tendency; 11±15ng/ml in the control, 25±22ng/ml in CHD, and 20±20ng/ml in CVD. The Lp (a) cocentration showed a significant positive correlation with β-TG and PF-4 levels in the CHD group, and similar correlation in the CVD group. In the fibrinolysic system, the fibrinogen value was significantly higher in the CHD ad CVD groups, while the tissue plasminogen activator (t-PA) value was significantly lower in the disease groups. 3) Fat loading study. Five M1 patients were loaded with either 50g/m² body surface of coconut oil or corn oil and followed up for 9 hours. The serum concentration of triglycerides (TG) was elevated by 28% and 78%, while that of Lp (a) decreased by 12% and 27%, respectively. The changes in TG and Lp (a) were negatively correlated (r=-0.790, p<0.001). 4) Lp (a) treatment study. After treatment of 15Ml patients with a nicotinic acid derivative of niceritrol, 750mg/day for 12 weeks, the Lp (a) value was decreased by 34%. In parallel, the β-TG and PF-4 levels were decreased by 26% (p<0.05) and 58% (NS), respectively. These changes in Lp (a) and β-TG, and PF-4 were correlated (p<0.001). These findings indicate that a close relationship between the Lp (a) concentration and platelet activities as observed in both the cross-sectional and challenge studies with fat loading and niceritrol treatment, and that Lp (a) interferes with fibrinolysis through increased fibrinogen and reduced t-PA concentrations, indicating that elevated Lp (a) promotes thrombogenesis by causing activation of platelets and inhibition of fibrinolysis in CHD and CVD.

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