Norihiro Sasaki

Dose-dependent hypolipidemic effect of an inhibitor of HMG-CoA reductase, pravastatin (CS-514)) in hypercholesterolemic subjects A double blind test

The hypolipidemic effect of a new HMG-CoA reductase inhibitor, pravastatin, was examined. The reductions of serum cholesterol and LDL-cholesterol were dose-dependent and significant differences were observed between placebo and 10 or 20 mg groups (P less than 0.01), and 10 and 20 mg (P less than 0.05) groups. The reduction rate of cholesterol after 8 weeks during medication was 16.1% in the 10 mg group, 20.5% in the 20 mg group compared to baseline serum cholesterol levels. LDL-cholesterol decreased by 23.9% in the 10 mg group, and 29.8% compared to baseline LDL-cholesterol in the 20 mg group. The lowering of total cholesterol was entirely attributed to a reduction in LDL-cholesterol.

Effect of pantethine on cholesterol ester metabolism in rat arterial wall.

The total serum cholesterol level in rats fed on a high cholesterol diet (HCD) for 16 weeks was markedly higher than that in rats fed on a normal diet (ND), but pantethine reduced the increased level in rats fed on HCD (P less than 0.05). Acid cholesterol esterase activity (acid CEase) of arterial wall homogenates from rats fed on HCD was significantly lower than that of rats fed on ND (P less than 0.005). Acid CEase activity in the arterial wall of rats fed on HCD for 8 weeks and then ND for 8 weeks was less than that of rats fed on ND for 16 weeks. Acid CEase activity in the arterial wall was increased in rats fed on pantethine-containing diet. The ratio of cholesterol ester synthesizing activity to neutral cholesterol esterase (neutral CEase) activity was higher in rats fed on NCD than in those fed on ND. The ratio was lower in rats on the pantethine-containing diet than in those on NCD. The relationship between hypercholesterolemia and lipid metabolism in the arterial wall and effects of pantethine are discussed on the basis of these results.

A familial hyperalphalipoproteinemia with low uptake of high density lipoproteins into peripheral lymphocytes

A patient with an extremely high level of high density lipoprotein (HDL)-cholesterol and HDLc-like particles in the serum is discussed. The patient was a 46-year-old female with a serum total cholesterol concentration of 382 mg/dl and HDL-cholesterol level of 214 mg/dl. The HDL-cholesterol levels of her mother, brother, sister and 2 of her daughters were 82 mg/dl, 82 mg/dl, 74 mg/dl, 82 mg/dl and 82 mg/dl, respectively (mean HDL-cholesterol levels of control subjects: 52 +/- 6 mg/dl in males and 55 +/- 8 mg/dl in females). Her serum apolipoprotein A-I and E levels were elevated. Zonal ultracentrifugal analysis of her serum lipoproteins showed that the increased level of HDL-cholesterol was mainly due to HDL2; HDLc-like particles were also recognized between the LDL and HDL fractions. The incorporation of the patients HDL and HDLc-like particles into cultured HepG2 cells was almost the same as that of HDL (1.063 less than d less than 1.21) from normal control serum. The incorporation of normal control HDL into the patients peripheral blood lymphocytes was markedly less than that into lymphocytes from normal controls. These findings are discussed in terms of the reason for hyperalphalipoproteinemia in this patient.

Lipid metabolism in arteriosclerotic arterial wall of rats

Arteriosclerotic lesions were formed in rat aorta by the administration of vitamin D2, a high-fat diet and a thyroid suppressing agent. This treatment increased the serum total cholesterol level to 12 times the control level. In the arteriosclerotic lesions that were induced the activities of lysosomal enzymes, such as acid phosphatase and acid lipase, were higher than in controls, that of acid cholesterol esterase was decreased, those of microsomal lipid-synthesizing enzymes--such as acyl-CoA synthetase and cholesterol ester synthesizing activity--were increased and that of neutral cholesterol esterase was decreased. These data suggest that lipid metabolism in arteriosclerotic lesions was changed, resulting in the accumulation of cholesterol esters in the aorta. Administration of high-fat diet and thyroid suppressing agent also increased the serum cholesterol levels to 12-fold the control level, but did not induce arteriosclerotic lesions. After this treatment the activities of hydrolyzing enzymes, such as acid and neutral cholesterol esterase and lipase, in the aorta increased, but the activities of lipid synthesizing enzymes also increased. These data suggest that lipid metabolism in the aorta in this condition changed to compensate for the large influx of serum lipids and to prevent arteriosclerosis. The roles of the serum lipid level, cell injury and lipid metabolism in the aorta in forming arteriosclerotic lesions are discussed on the basis of these results.

Effects of chloroquine on the metabolism of phosphatidylcholine associated with low density lipoprotein in arterial smooth muscle cells

Phospholipid associated with LDL (LDL-phospholipid) has been suggested to affect metabolism of LDL in arterial smooth muscle cells. However, the metabolism of LDL-phosphatidylcholine in these cells has not been well clarified. We compared the metabolic pathway of LDL-phosphatidylcholine with that of cholesteryl ester associated with LDL (LDL-cholesteryl ester) in rabbit arterial smooth muscle cells by incubating the cells in the absence or presence of chloroquine, an inhibitor of lysosomal function. When the cells were incubated with LDL-[3H]cholesterol linoleate in the absence of chloroquine, 26.6 and 51.4% of incorporated radioactivity was found as cholesteryl ester in the lysosome-rich and microsome-rich fractions, respectively. When the cells were incubated in the presence of 50 microM chloroquine, the radioactivity found as cholesteryl ester in the lysosome-rich fraction increased to 45.5% while that in microsome-rich fraction decreased to 21.4%, indicating that LDL-cholesteryl ester accumulated in lysosomes as a consequence of inhibition of lysosomal function. When the cells were incubated with LDL-[14C]linoleoyl phosphatidylcholine in the absence of chloroquine, 25.1% of incorporated radioactivity was found as phosphatidylcholine in the lysosome-rich fraction and 24.8% in the cytosol-rich fraction. When the cells were incubated in the presence of chloroquine, phosphatidylcholine-associated radioactivity found in the lysosome-rich and cytosol-rich fractions changed only to 28.8% and 26.1%, respectively, showing that LDL-phosphatidylcholine did not accumulate in lysosomes when lysosomal function was inhibited. In conclusion, these data indicate that LDL-phosphatidylcholine, in contrast to LDL-cholesteryl ester, is not only hydrolyzed in lysosomes, but also at other subcellular sites.

Effect of hyercholesterolemia on cholinephosphotransferase activity in rabbit and rat vessel walls

The activity of cholinephosphotransferase (EC 2.7.8.2, CPT) which catalyses de novo synthesis of phosphatidylcholine (PC) was studied in aortas of rabbits and rats, and in brain microvessels of rabbits with a cholesterol feeding-induced hypercholesterolemia. Cholesterol feeding produced a marked atheromatous change in rabbit aortas but not in rat aortas. The aortas of cholesterol-fed rabbits displayed a significantly higher CPT activity than the controls. On the other hand, the aortic CPT activity of cholesterol-fed rats was not different from that of control rats. The brain microvessels of cholesterol-fed rabbits having atheromatous aortic lesions did not show any lipid deposition, and CPT activity was similar to that of control rabbits. A tocopherol-deficient, high-cholesterol diet produced microscopical lipid deposits in rat aortas, and CPT activity of these aortas was significantly higher than that of aortas of rats on tocopherol-supplemented diets containing either a normal or high amount of cholesterol. The increase in CPT activity in atheromatous lesion might be closely related to lipid deposition in vessel walls and may be a cause of the increase in PC content in these lesions. Further studies are required to clarify the mechanism of activation of CPT activity in atheromatous conditions.