Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that accelerates cholesterol biosynthesis
Regulation of hepatic cholesterol synthesis by a novel protein (SPF) that accelerates cholesterol biosynthesis
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DOI：
10.1096/fj.06-6368fje
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发表时间：
2006-12-01
期刊：
影响因子：
4.8
通讯作者：
Arai, Hiroyuki
中科院分区：
文献类型：
--
作者：
Shibata, Norihito;Jishage, Kou-ichi;Arai, Hiroyuki
上清蛋白因子（SPF）是一种新的胆固醇生物合成促进蛋白，在肝脏和小肠中表达.在这里，我们报告SPF的生理作用，通过使用SPF缺陷小鼠。尽管在普通饲料喂养的Spf（-/-）和野生型（WT）小鼠中血浆胆固醇水平相似，但禁食显著降低了Spf（-/-）小鼠的血浆胆固醇水平，但在WT小鼠中没有。虽然禁食降低了WT小鼠的肝脏胆固醇合成率，但在Spf（-/-）小鼠中观察到更明显的降低。WT和Spf（-/-）小鼠的胆固醇生成酶的表达均受到禁食的显著抑制。相反，WT小鼠肝脏SPF表达通过禁食以过氧化物酶体增殖物激活受体α（PPAR-alpha）依赖性方式上调。这些结果表明，在WT小鼠中，禁食条件下肝脏胆固醇合成的减少至少部分地被SPF上调所补偿。贝特类作为一种PPAR-alpha激动剂，广泛用作降血糖药物，在Spf（-/-）小鼠中可使肝脏胆固醇合成和血浆胆固醇水平降低约一半，但在WT小鼠中则不然。这些发现表明，贝特类和SPF抑制剂的联合给药不仅可以降低血浆甘油三酯，还可以降低胆固醇水平，表明SPF是一种有前途的降胆固醇药物靶点。
Supernatant protein factor (SPF) is a novel cholesterol biosynthesis- accelerating protein expressed in liver and small intestine. Here, we report on the physiological role of SPF by using Spf-deficient mice. Although plasma cholesterol levels were similar in chow-fed Spf(-/-) and wild-type (WT) mice, fasting significantly decreased plasma cholesterol levels in Spf(-/-) mice but not in WT mice. While fasting reduced hepatic cholesterol synthesis rate in WT mice, a more pronounced reduction was observed in Spf(-/-) mice. The expression of cholesterogenic enzymes was dramatically suppressed by fasting both in WT and Spf(-/-) mice. In contrast, hepatic SPF expression of WT mice was up-regulated by fasting in peroxisome proliferator-activated receptor alpha (PPAR-alpha)-dependent manner. These results indicate that in WT mice, the decrease of hepatic cholesterol synthesis under fasting conditions is at least in part compensated by SPF up-regulation. Fibrates, which function as a PPAR-alpha agonist and are widely used as hypotriglycemic drugs, reduced hepatic cholesterol synthesis and plasma cholesterol levels by approximately one-half in Spf(-/-) mice but not in WT mice. These findings suggest that co-administration of fibrates and an SPF inhibitor may reduce not only plasma triglyceride but also cholesterol levels, indicating that SPF is a promising hypocholesterolemic drug target.