A RECEPTOR-MEDIATED PATHWAY FOR CHOLESTEROL HOMEOSTASIS
A RECEPTOR-MEDIATED PATHWAY FOR CHOLESTEROL HOMEOSTASIS
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DOI：
10.1126/science.3513311
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发表时间：
1986-04-04
期刊：
影响因子：
56.9
通讯作者：
GOLDSTEIN, JL
中科院分区：
文献类型：
--
作者：
BROWN, MS;GOLDSTEIN, JL
1901年，一位名叫阿奇博尔德·加罗德的内科医生在给一位黑尿病人做了检查后，提出一个突变基因可以在生化途径中产生一种不连续的阻滞，他称之为”先天性代谢缺陷“。“加罗德的杰出洞察力预见了比德尔和塔特姆40年前提出的一个基因一个酶的概念。同样，化学家莱纳斯·鲍林（Linus Pauling）和内科医生弗农·英格拉姆（Vernon Ingram）通过对镰状细胞性贫血患者的研究，发现突变基因会改变蛋白质的氨基酸序列。很明显，生物学的许多基本进展都是由对人类遗传疾病的深刻研究产生的（1）。我们于1972年开始工作，试图了解一种人类遗传疾病，家族性高胆固醇血症（FH）。在患有这种疾病的患者中，血液中胆固醇的浓度比正常水平高出许多倍，并且在生命早期发生心脏病发作。我们推测，这种显性遗传性疾病是由于胆固醇合成的终产物抑制失败所致。这种可能性令我们着迷，因为反馈调节的遗传缺陷以前在人类或动物中没有观察到，我们希望对这种疾病的研究可能会揭示基本的调节机制。
IN 1901, AFTER STUDYING A PATIENT WITH BLACK URINE, A physician named Archibald Garrod suggested thata single mutant gene can produce a discrete block in a biochemical pathway, which he called an" inborn error of metabolism." Garrod's brilliant insight anticipated by40 years the one gene-one enzyme concept of Beadle and Tatum. Similarly, the chemist Linus Pauling and the physicianVernon Ingram, through study of patients with sickle cell anemia, showed that mutant genes alter the amino acid sequences of proteins. Clearly, many fundamental advances in biology were spawned by perceptive studies of human genetic diseases (1).We began our work in 1972 in an attempt to understand a human genetic disease, familial hypercholesterolemia (FH). In patients with this disease, the concentration ofcholesterol in the blood is elevated many times above normal and heart attacks occur early in life. We postulated that this dominantly inherited disease results from a failure of end-product repression of cholesterol synthesis. The possibility fascinated us because genetic defects in feedback regulation had not been observed previously in humans or animals, and we hoped that study of this disease might throw lighton fundamental regulatory mechanisms.