Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice
Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice
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DOI：
10.1194/jlr.m200489-jlr200
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发表时间：
2003-05-01
影响因子：
6.5
通讯作者：
Salen, G
中科院分区：
文献类型：
--
作者：
Erickson, SK;Lear, SR;Salen, G
胆固醇7 α-羟化酶是胆汁酸合成的限速酶，与动脉粥样硬化的遗传易感性有关。编码具有这种活性的蛋白质的基因CYP 7A 1通常仅在肝细胞中表达，并且受到高度调节。我们的cyp 7A 1基因敲除小鼠群体，作为一个年轻的成年人在一个普通饮食，是高胆固醇血症。对这些小鼠进行了广泛的表征，以了解cyp 7A 1如何影响不同组织区室中的脂质和胆汁酸稳态，以及性别是否起着修饰作用。雄性和雌性cyp 7A 1缺陷小鼠的肝脏LDL受体减少，肝脏胆固醇合成不变，肠道胆固醇合成和胆汁酸转运蛋白增加，粪便胆汁酸减少，但粪便固醇增加。在雌性动物中，cyp 7A 1缺乏还导致肝脏脂肪酸代谢发生变化，肝小管胆汁酸转运蛋白Bsep降低，胆囊胆汁成分改变为致石性。两者合计，数据表明，cyp 7A 1缺陷导致两种性别的促动脉粥样硬化表型，并导致女性的促结石表型。
Cholesterol 7alpha-hydroxylase, a rate-limiting enzyme for bile acid synthesis, has been implicated in genetic susceptibility to atherosclerosis. The gene, CYP7A1, encoding a protein with this activity, is expressed normally only in hepatocytes and is highly regulated. Our cyp7A1 gene knockout mouse colony, as young adults on a chow diet, is hypercholesterolemic. These mice were characterized extensively to understand how cyp7A1 affects lipid and bile acid homeostasis in different tissue compartments and whether gender plays a modifying role. Both male and female cyp7A1-deficient mice had decreased hepatic LDL receptors, unchanged hepatic cholesterol synthesis, increased intestinal cholesterol synthesis and bile acid transporters, and decreased fecal bile acids but increased fecal sterols. In females, cyp7A1 deficiency also caused changes in hepatic fatty acid metabolism, decreased hepatic canalicular bile acid transporter, Bsep, and gallbladder bile composition altered to a lithogenic profile. Taken together, the data suggest that cyp7A1 deficiency results in a proatherogenic phenotype in both genders and leads to a prolithogenic phenotype in females.