Shefer S, Salen G, Bullock J, Nguyen L B, Ness G C, Vhao Z, Belamarich P F, Chowdhary I, Lerner S, Batta A K
Sammy Davis Jr. National Liver Institute, University of Medicine and Newark 07103.
Hepatology. 1994 Jul;20(1 Pt 1):213-9. doi: 10.1016/0270-9139(94)90155-4.
We investigated hepatic cholesterol homeostasis in four homozygous sitosterolemic subjects from two unrelated families who showed enhanced absorption, diminished removal and increased tissue and plasma concentrations of sitosterol (24-ethyl cholesterol). Measurements of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were correlated with steady state messenger RNA levels and related to cholesterol 7 alpha-hydroxylase activities in the sitosterolemic homozygotes and nine controls. Similar determinations were made in rats infused intravenously with sitosterol so that hepatic and plasma sitosterol concentrations increased to about 10% of total sterols to resemble the human disease sitosterolemia. In the four sitosterolemic homozygotes, hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities were markedly reduced (12% of normal), and steady state 3-hydroxy-3-methylglutaryl coenzyme A reductase messenger RNA levels barely detected. In contrast, hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activities and messenger RNA levels were not decreased in rats with similarly elevated hepatic sitosterol concentrations. However, hepatic cholesterol 7 alpha-hydroxylase activity was inhibited 30% in both the sitosterolemic homozygotes and rats with high liver sitosterol concentrations. Plasma cholesterol concentrations increased 120% in the sitosterol-infused rats and 29% in the untreated human homozygotes. These results demonstrate that high-tissue sitosterol concentrations do not inhibit hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activityor steady state messenger RNA levels and that they competitively block cholesterol 7 alpha-hydroxylase activity and raise plasma cholesterol levels. Thus the deficiency of 3-hydroxy-3-methylglutaryl coenzyme A reductase in the liver of sitosterolemic homozygotes is inherited and not due to the hepatic accumulation of sitosterol.(ABSTRACT TRUNCATED AT 250 WORDS)
我们对来自两个不相关家族的四名纯合子谷甾醇血症患者的肝脏胆固醇稳态进行了研究，这些患者表现出吸收增强、清除减少以及谷甾醇（24-乙基胆固醇）在组织和血浆中的浓度增加。在纯合子谷甾醇血症患者和九名对照中，测量肝脏3-羟基-3-甲基戊二酰辅酶A还原酶活性，并将其与稳态信使RNA水平相关联，并与胆固醇7α-羟化酶活性相关。对静脉注射谷甾醇的大鼠进行了类似测定，以使肝脏和血浆谷甾醇浓度增加至总甾醇的约10%，以模拟人类疾病谷甾醇血症。在四名纯合子谷甾醇血症患者中，肝脏3-羟基-3-甲基戊二酰辅酶A还原酶活性显著降低（为正常水平的12%），稳态3-羟基-3-甲基戊二酰辅酶A还原酶信使RNA水平几乎检测不到。相比之下，肝脏谷甾醇浓度同样升高的大鼠中，肝脏3-羟基-3-甲基戊二酰辅酶A还原酶活性和信使RNA水平并未降低。然而，纯合子谷甾醇血症患者和肝脏谷甾醇浓度高的大鼠中，肝脏胆固醇7α-羟化酶活性均被抑制30%。静脉注射谷甾醇的大鼠血浆胆固醇浓度增加了120%，未经治疗的人类纯合子增加了29%。这些结果表明，高组织谷甾醇浓度不会抑制肝脏3-羟基-3-甲基戊二酰辅酶A还原酶活性或稳态信使RNA水平，并且它们竞争性地阻断胆固醇7α-羟化酶活性并提高血浆胆固醇水平。因此，纯合子谷甾醇血症患者肝脏中3-羟基-3-甲基戊二酰辅酶A还原酶的缺乏是遗传性的，而非由于谷甾醇在肝脏中的积累。（摘要截短于250字）
