Ness G C, Lopez D, Chambers C M, Zhao Z, Beach D L, Ko S S, Trzaskos J M
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Florida, Tampa 33612, USA.
Arch Biochem Biophys. 1998 Sep 15;357(2):259-64. doi: 10.1006/abbi.1998.0843.
The mechanisms by which oxylanosterols regulate expression of hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and lower serum cholesterol levels were examined by using a novel nonmetabolizable oxylanosterol mimic, 15-oxa-32-vinyl-lanost-8-ene-3 beta, 32 diol (DMP 565). This compound, unlike other nonmetabolizable oxylanosterols, is not a substrate for lanosterol 14 alpha-methyl demethylase. Feeding rats a diet supplemented with 0.02% DMP 565 markedly decreased HMG-CoA reductase immunoreactive protein and enzyme activity levels without affecting mRNA levels. The rate of reductase protein degradation was unaffected. However, the rate of translation was reduced to less than 20% of control. Thus, DMP 565 appears to regulate hepatic HMG-CoA reductase gene expression primarily at the level of translation. The pronounced inhibition of HMG-CoA reductase by DMP 565 resulted in a compensatory increase in the functioning of the hepatic low density lipoprotein (LDL) receptor, possibly by increased cycling, as evidenced by a marked increase in the rate of degradation of the LDL receptor. The half-life of the receptor was decreased from over 7 h to only 1 h in animals receiving DMP 565. This increase in the rate of degradation occurred without a change in the steady state level of the receptor. Addition of dietary cholesterol attenuated the increased turnover of the LDL receptor. These effects on the hepatic LDL receptor have also been observed with HMG-CoA reductase inhibitors (G. C. Ness et al., 1996, Arch. Biochem, Biophys. 325, 242-248). However, the effect of DMP 565 on the rate of degradation of the hepatic LDL receptor was of a greater magnitude when equal doses of the drugs were used. These regulatory actions of DMP 565 provide, in part, an explanation for the observed hypocholesterolemic action of this compound.
通过使用一种新型的不可代谢的氧代甾醇类似物15-氧杂-32-乙烯基-羊毛甾-8-烯-3β,32-二醇（DMP 565），研究了氧代甾醇调节肝脏3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶表达并降低血清胆固醇水平的机制。与其他不可代谢的氧代甾醇不同，该化合物不是羊毛甾醇14α-甲基脱甲基酶的底物。给大鼠喂食添加0.02% DMP 565的饮食可显著降低HMG-CoA还原酶免疫反应性蛋白和酶活性水平，而不影响mRNA水平。还原酶蛋白降解速率未受影响。然而，翻译速率降至对照的20%以下。因此，DMP 565似乎主要在翻译水平调节肝脏HMG-CoA还原酶基因表达。DMP 565对HMG-CoA还原酶的显著抑制导致肝脏低密度脂蛋白（LDL）受体功能的代偿性增加，可能是通过增加循环，这表现为LDL受体降解速率的显著增加。在接受DMP 565的动物中，受体的半衰期从超过7小时降至仅1小时。这种降解速率的增加在受体的稳态水平没有变化的情况下发生。添加膳食胆固醇减弱了LDL受体周转的增加。用HMG-CoA还原酶抑制剂也观察到了对肝脏LDL受体的这些影响（G.C.Ness等人，1996年，《生物化学与生物物理学档案》325卷，242 - 248页）。然而，当使用等量药物时，DMP 565对肝脏LDL受体降解速率的影响幅度更大。DMP 565的这些调节作用部分解释了该化合物所观察到的降胆固醇作用。
