Kasim S E, LeBoeuf R C, Khilnani S, Tallapaka L, Dayananda D, Jen K L
Department of Medicine, Wayne State University, Detroit, MI.
J Lipid Res. 1992 Jan;33(1):1-7.
Inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase have been approved for treatment of hypercholesterolemia in humans. This class of therapeutic agents, in addition to lowering plasma cholesterol, reduces plasma triglyceride levels. We have investigated the mechanism of triglyceride-lowering effect of lovastatin in the hypertriglyceridemic state by using a rodent model of hypertriglyceridemia and obesity, the Zucker obese (fa/fa) rat. Lovastatin treatment (4 mg/kg), as compared to placebo, caused a 338% reduction in plasma triglyceride (146 +/- 5 vs. 494 +/- 76 mg/dl), a 58% decrease in total cholesterol (99 +/- 13 vs. 156 +/- 18 mg/dl), and a 67% reduction in high density lipoprotein (HDL)-cholesterol (69 +/- 8 vs. 115 +/- 15 mg/dl). The fall seen in plasma triglyceride was due to a decrease in hepatic secretion of very low density lipoproteins (VLDL), determined after blocking the clearance of triglyceride-rich lipoproteins with Triton WR-1339. Lovastatin treatment did not affect either the activities of hepatic lipogenic enzymes, glucose-6-phosphate dehydrogenase, or malic enzyme, or the activities of the lipolytic enzymes of adipose tissue, lipoprotein lipase, or liver, hepatic triglyceride lipase. Supplementation of mevalonolactone in the diet partially reversed the changes in plasma triglyceride (265 +/- 37 vs. 146 +/- 5 mg/dl), but not in total or HDL-cholesterol. These data demonstrate that, in the hypertriglyceridemic Zucker rat model, HMG-CoA reductase inhibitors reduce the rate of secretion of VLDL and this effect can be partially reversed by administration of mevalonolactone.
3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶抑制剂已被批准用于治疗人类高胆固醇血症。这类治疗药物除了能降低血浆胆固醇外，还能降低血浆甘油三酯水平。我们通过使用高甘油三酯血症和肥胖的啮齿动物模型——Zucker肥胖（fa/fa）大鼠，研究了洛伐他汀在高甘油三酯血症状态下降低甘油三酯作用的机制。与安慰剂相比，洛伐他汀治疗（4毫克/千克）使血浆甘油三酯降低了338%（146±5对494±76毫克/分升），总胆固醇降低了58%（99±13对156±18毫克/分升），高密度脂蛋白（HDL）胆固醇降低了67%（69±8对115±15毫克/分升）。血浆甘油三酯的下降是由于极低密度脂蛋白（VLDL）肝分泌减少，这是在用Triton WR-1339阻断富含甘油三酯脂蛋白的清除后测定的。洛伐他汀治疗既不影响肝脂肪生成酶、葡萄糖-6-磷酸脱氢酶或苹果酸酶的活性，也不影响脂肪组织、脂蛋白脂肪酶或肝脏（肝甘油三酯脂肪酶）的脂解酶活性。饮食中补充甲羟戊酸内酯可部分逆转血浆甘油三酯的变化（265±37对146±5毫克/分升），但对总胆固醇或HDL胆固醇无此作用。这些数据表明，在高甘油三酯血症的Zucker大鼠模型中，HMG-CoA还原酶抑制剂降低了VLDL的分泌速率，且这种作用可通过给予甲羟戊酸内酯部分逆转。
