Nguyen L B, Shefer S, Salen G, Ness G C, Tint G S, Zaki F G, Rani I
Department of Medicine, University of Medicine and Dentistry-New Jersey Medical School, Newark 07103.
J Clin Invest. 1990 Sep;86(3):923-31. doi: 10.1172/JCI114794.
We examined the relationship between cholesterol biosynthesis and total and high affinity LDL binding in liver specimens from two sitosterolemic and 12 healthy control subjects who died unexpectedly and whose livers became available when no suitable recipient for transplantation was identified. Accelerated atherosclerosis, unrestricted intestinal sterol absorption, increased plasma and tissue plant sterol concentrations, and low cholesterol synthesis characterize this disease. Mean total microsomal HMG-CoA reductase (rate-control controlling enzyme for cholesterol biosynthesis) activity was sevenfold higher (98.1 +/- 28.8 vs. 15.0 +/- 2.0 pmol/mg protein per min) and microsomal enzyme protein mass was eightfold larger (1.43 +/- 0.41 vs. 0.18 +/- 0.04 relative densitometric U/mg protein) in 11 controls than the average for two sitosterolemic liver specimens. HMG-CoA reductase mRNA probed with pRED 227 and pHRED 102 was decreased to barely detectable levels in the sitosterolemic livers. In addition, there was a 50% decrease in the rate [2-14C]mevalonic acid was converted to cholesterol by sitosterolemic liver slices compared with controls (112 vs. 224 +/- 32 pmol/g liver per h). In contrast, average total LDL binding was 60% greater (326 vs. 204 +/- 10 ng/mg), and high affinity (receptor-mediated) binding 165% more active (253 vs. 95.1 +/- 8.2 ng/mg) in two sitosterolemic liver membrane specimens than the mean for 12 controls. Liver morphology was intact although sitosterolemic hepatocytes and microsomes contained 24 and 14% less cholesterol, respectively, and 10-100 times more plant sterols and 5 alpha-stanols than control specimens. We postulate that inadequate cholesterol biosynthesis is an inherited abnormality in sitosterolemia and may be offset by augmented receptor-mediated LDL catabolism to supply cellular sterols that cannot be formed.
我们研究了2名谷甾醇血症患者和12名意外死亡且因未找到合适移植受体而获得肝脏的健康对照者肝脏标本中胆固醇生物合成与总低密度脂蛋白（LDL）结合及高亲和力LDL结合之间的关系。该疾病的特征为动脉粥样硬化加速、肠道甾醇吸收不受限制、血浆和组织植物甾醇浓度升高以及胆固醇合成降低。11名对照者的平均微粒体HMG-CoA还原酶（胆固醇生物合成的速率控制酶）活性比2份谷甾醇血症肝脏标本的平均值高7倍（98.1±28.8对15.0±2.0 pmol/mg蛋白质每分钟），微粒体酶蛋白量比其大8倍（1.43±0.41对0.18±0.04相对光密度单位/mg蛋白质）。用pRED 227和pHRED 102探针检测时，谷甾醇血症肝脏中HMG-CoA还原酶mRNA降至几乎检测不到的水平。此外，与对照相比，谷甾醇血症肝脏切片将[2-¹⁴C]甲羟戊酸转化为胆固醇的速率降低了50%（112对224±32 pmol/g肝脏每小时）。相反，2份谷甾醇血症肝脏膜标本的平均总LDL结合比12名对照者的平均值高60%（326对204±10 ng/mg），高亲和力（受体介导）结合活性高165%（253对95.1±8.2 ng/mg）。尽管谷甾醇血症肝细胞和微粒体中的胆固醇分别比对照标本少24%和14%，植物甾醇和5α-甾烷醇比对照标本多10至100倍，但肝脏形态完整。我们推测胆固醇生物合成不足是谷甾醇血症的一种遗传异常，可能通过增强受体介导的LDL分解代谢来弥补无法合成的细胞甾醇。
