Yumiko Asami

Hypolipidemic Effect of Taurine in Stroke-Prone Spontaneously Hypertensive Rats

The hypolipidemic and antiatherosclerotic effects of taurine were investigated in genetically hypertensive rats: strokeprone spontaneously hypertensive rats (SHRSP). SHRSP were fed a hypercholesterolemic (HC) diet supplemented with 3% taurine for 50 days, and serum cholesterol was monitored. Cholesterol content and enzymatic activity responsible for cholesterol synthesis and metabolism were also determined in the liver, aorta, and intestine. Taurine prevented increases in the cholesterol level of the serum, liver, and aorta induced by a HC diet. Severe fat deposits of the mesenteric arteries induced by a HC diet were improved by the taurine treatment, showing the hypolipidemic and antiatherosclerotic effects of taurine. Taurine enhanced the activity of cholesterol 7 alpha-hydroxylase, a rate-limiting enzyme of bile acid synthesis, and stimulated bile acid production. These results suggest that taurine stimulates bile acid synthesis, which is closely related to the enhancement of cholesterol 7 alpha-hydroxylase activity, and thereby reduces serum cholesterol. In addition, a decrease in the intestinal acyl CoA:cholesterol acyltransferase activity by taurine suggests that the inhibition of cholesterol absorption may also be related to the hypolipidemic effect of taurine, in part.

Inhibitory effect of TS-962 on the formation of early atherosclerotic lesions in high fat-fed hyperlipidemic hamsters.

The hypocholesterolemic and anti-atherosclerotic effect of TS-962, a specific ACAT inhibitor, was investigated in a hamster model fed a high fat diet containing 10% coconut oil and 0.05% cholesterol. Lipid accumulated atherosclerotic lesions were detected by using oil red O staining in the lesion-prone aortic arch. A high dose, estimated to be 15 mg/kg, of TS-962 decreased serum cholesterol to normal levels with reduction of liver cholesterol contents below normal levels, and as a consequence, entirely inhibited the lipid accumulation in the aortic arch. Furthermore, a low dose, estimated to be 1.5 mg/kg, of TS-962 remarkably inhibited aortic lipid accumulation by 73% compared with the control group, without changing either serum cholesterol level or liver cholesterol content. These findings suggest that TS-962 is effective in the primary prevention of atherosclerosis by directly suppressing the formation of foam cells in arteries.

HL-004, the ACAT inhibitor, prevents the progression of atherosclerosis in cholesterol-fed rabbits

HL-004, N-(2,6-diisopropylphenyl) tetradecylthioacetamide, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was evaluated concerning the possible prevention of hyperlipidemia and atherosclerosis in 1% cholesterol-fed rabbits. HL-004 (0.2, 5 and 25 mg/kg) was orally administered once a day for 12 weeks. HL-004 inhibited the rise of total serum cholesterol at a dose of 5 mg/kg and over. In the thoracic aorta, HL-004 at the doses of 5 mg/kg and 25 mg/kg reduced the total cholesterol content by 56.3% and 84.2% compared with control, and decreased ACAT activity, dose-dependently. HL-004 also attenuated the development of aortic lesions. The area of atherosclerotic lesions was reduced by 30.3% with 5 mg/kg of HL-004 and 100% with 25 mg/kg. In this study, we suggest that the main reason for HL-004 preventing the progression of atherosclerosis is its hypocholesterolemic effect due to the inhibition of cholesterol absorption in the intestine.

The hypolipidemic action of the ACAT inhibitor HL-004 in hamsters fed normal chow.

1. A novel ACAT (acyl-CoA: cholesterol acyltransferase) inhibitor, HL-004, exhibited a strong inhibitory effect on the hepatic and intestinal ACAT, but was less effective on the adrenal ACAT in vitro. 2. HL-004 selectively decreased serum VLDL cholesterol, and inhibited hepatic ACAT activity in hamsters fed normal chow. 3. These results suggest that the cholesterol-lowering effect of HL-004 can be attributed to a decrease in hepatic VLDL secretion via inhibition of ACAT.

The ACAT Inhibitor HL-004 Inhibits Cholesterol Absorption and Lowers Serum Cholesterol in Rats

1. HL-004 decreased absorption of cholesteryl ester from the intestine into the lymph in a rat lymph-fistula model. 2. HL-004 reduced serum cholesterol level in acute cholesterol-fed rats. 3. HL-004 simultaneously decreased hepatic cholesteryl ester content and increased free cholesterol in cholesterol-fed rats. 4. These findings suggest that: (1) the hypocholesterolemic effect of HL-004 is principally due to inhibition of cholesterol absorption via inhibition of ACAT in the intestine; and (2) changes in hepatic cholesterol metabolism due to direct inhibition by HL-004 of hepatic ACAT may account in part for reduction of serum cholesterol level by HL-004.