Murakami S, Yamagishi I, Sato M, Tomisawa K, Nara Y, Yamori Y
Medicinal Research Laboratories, Taisho Pharmaceutical Co. Ltd., Ohmiya, Japan.
Atherosclerosis. 1997 Aug;133(1):97-104. doi: 10.1016/s0021-9150(97)00121-4.
The effect of the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor HL-004 on bile acid production was studied during the regression phase of pre-established hypercholesterolemia in stroke-prone spontaneously hypertensive rats (SHRSP). These rats were fed a hypercholesterolemic diet containing 5% cholesterol, 2% cholic acid, and 20% suet for 30 days to induce hypercholesterolemia. The regression phase was started by switching the diet to normal chow, followed by another 30 days of the diet. The decrease in serum cholesterol level was accelerated by treatment with 0.09% HL-004. At the end of regression, hepatic ACAT activity was significantly lower in the HL-004 treated animals, an event concomitant with the significant decrease in cholesteryl ester content in the liver. In contrast hepatic cholesterol 7 alpha-hydroxylase activity was maintained at a higher level in the HL-004 treated animals. HL-004 increased the secretion of bile acid and biliary lipids in bile duct-cannulated SHRSP. In HepG2:cells, HL-004 at 1-30 microM dose-dependently stimulated bile acid synthesis from [3H]cholesterol. When cholesterol 7 alpha-hydroxylase activity of the liver was compared ex vivo in the presence and in the absence of exogenous cholesterol, it was suggested that the higher 7 alpha-hydroxylase activity of the HL-004 group could be attributed not only to expansion of the endogenous cholesterol pool, which may be the result of hepatic ACAT inhibition by HL-004 but to the direct effect of HL-004 on bile acid production. Thus, HL-004 accelerates the regression of hypercholesterolemia, an event which may be related to the stimulation of bile acid production in the liver.
在易患中风的自发性高血压大鼠（SHRSP）已建立的高胆固醇血症消退阶段，研究了酰基辅酶A：胆固醇酰基转移酶（ACAT）抑制剂HL-004对胆汁酸生成的影响。这些大鼠喂食含5%胆固醇、2%胆酸和20%羊油的高胆固醇饮食30天以诱导高胆固醇血症。消退阶段通过将饮食换成正常饲料开始，随后再持续30天。用0.09%的HL-004治疗可加速血清胆固醇水平的降低。在消退期末，HL-004治疗组动物的肝脏ACAT活性显著降低，这一情况与肝脏中胆固醇酯含量的显著降低同时出现。相反，HL-004治疗组动物的肝脏胆固醇7α-羟化酶活性维持在较高水平。HL-004增加了胆管插管的SHRSP胆汁中胆汁酸和胆脂质的分泌。在HepG2细胞中，1-30微摩尔剂量的HL-004可剂量依赖性地刺激[3H]胆固醇合成胆汁酸。当在有和没有外源性胆固醇的情况下对肝脏胆固醇7α-羟化酶活性进行体外比较时，提示HL-004组较高的7α-羟化酶活性不仅可归因于内源性胆固醇池的扩大（这可能是HL-004抑制肝脏ACAT的结果），还可归因于HL-004对胆汁酸生成的直接作用。因此，HL-004加速了高胆固醇血症的消退，这一情况可能与刺激肝脏胆汁酸生成有关。
