Park Tae-Sik, Panek Robert L, Rekhter Mark D, Mueller Sandra Bak, Rosebury Wendy S, Robertson Andrew, Hanselman Jeffrey C, Kindt Erick, Homan Reynold, Karathanasis Sotirios K
Cardiovascular Pharmacology, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA.
Atherosclerosis. 2006 Dec;189(2):264-72. doi: 10.1016/j.atherosclerosis.2005.12.029. Epub 2006 Feb 2.
Plasma sphingomyelin (SM) has been suggested as a risk factor for coronary heart disease independent of cholesterol levels. A decrease of SM in lipoproteins is known to improve the activities of lecithin:cholesterol acyltransferase (LCAT) and lipoprotein lipase (LPL) in vitro. Inhibition of SM biosynthesis may reduce lipoprotein SM content and thus improve cholesterol distribution in lipoproteins by enhancing reverse cholesterol transport and clearance of triglyceride-rich lipoproteins. To examine this hypothesis, ApoE KO mice were fed a western diet and treated for 4 weeks with various concentrations of myriocin, a specific inhibitor of serine palmitoyltransferase. Myriocin treatment lowered plasma cholesterol and TG levels in a dose-dependent manner. In addition, myriocin treatment reduced cholesterol contents in VLDL and LDL and elevated HDL-cholesterol. Observed lipid-lowering effects of myriocin were associated with suppression of HMG CoA reductase and fatty acid synthase via reduced levels of SREBP-1 RNA and protein. Induction of apoAI and lecithin:cholesterol acytransferase (LCAT) in the liver by myriocin was associated with an increased HDL. Lesion area and macrophage area were also diminished in the cuffed femoral artery of ApoE KO mice. In conclusion, inhibition of sphingolipid biosynthesis can be a novel therapeutic target for dyslipidemia and atherosclerosis.
血浆鞘磷脂（SM）已被认为是冠心病的一个独立于胆固醇水平的危险因素。已知脂蛋白中SM的减少可在体外改善卵磷脂胆固醇酰基转移酶（LCAT）和脂蛋白脂肪酶（LPL）的活性。抑制SM生物合成可能会降低脂蛋白SM含量，从而通过增强逆向胆固醇转运和富含甘油三酯脂蛋白的清除来改善脂蛋白中的胆固醇分布。为了验证这一假设，给载脂蛋白E基因敲除（ApoE KO）小鼠喂食西式饮食，并用不同浓度的鞘氨醇（一种丝氨酸棕榈酰转移酶的特异性抑制剂）处理4周。鞘氨醇处理以剂量依赖的方式降低了血浆胆固醇和甘油三酯水平。此外，鞘氨醇处理降低了极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）中的胆固醇含量，并提高了高密度脂蛋白胆固醇（HDL-胆固醇）水平。观察到的鞘氨醇的降脂作用与通过降低固醇调节元件结合蛋白1（SREBP-1）RNA和蛋白质水平对3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶和脂肪酸合酶的抑制有关。鞘氨醇在肝脏中诱导载脂蛋白AI（apoAI）和卵磷脂胆固醇酰基转移酶（LCAT）与HDL增加有关。在ApoE KO小鼠的股动脉套环处，病变面积和巨噬细胞面积也减小。总之，抑制鞘脂生物合成可能是治疗血脂异常和动脉粥样硬化的一个新的治疗靶点。
