Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice.
Transgenic expression of cholesterol 7alpha-hydroxylase in the liver prevents high-fat diet-induced obesity and insulin resistance in mice.
复制标题
肝脏中胆固醇7alpha-羟化酶在肝脏中的转基因表达可防止小脂饮食诱导的肥胖和胰岛素抵抗。
DOI：
10.1002/hep.23721
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发表时间：
2010-08
期刊：
影响因子：
13.5
通讯作者：
Chiang, John Y. L.
中科院分区：
文献类型：
--
作者：
Li, Tiangang;Owsley, Erika;Matozel, Michelle;Hsu, Peter;Novak, Colleen M.;Chiang, John Y. L.
胆固醇7α-羟基酶是胆汁酸生物合成途径中的限速酶，在肝脏中将胆固醇转化为胆汁酸。最近的研究表明，胆汁酸可能在维持血脂、血糖和能量动态平衡方面发挥重要作用。然而，CYP7A1在肥胖和糖尿病的发生发展中的作用目前尚不清楚。在这项研究中，我们证明了在肝脏中过度表达Cyp7a1的转基因小鼠[即Cyp7a1转基因(Cyp7a1-TG)小鼠]对高脂饮食(HFD)诱导的肥胖、脂肪肝和胰岛素抵抗具有抵抗力。Cyp7a1-TG小鼠表现出肝脏胆固醇分解代谢增加和胆汁酸池增加。Cyp7a1-TG小鼠肝脏极低密度脂蛋白分泌增加，但维持血浆甘油三酯稳态。基因表达分析表明，高脂饲料喂养的Cyp7a1-TG小鼠肝脏中几个关键的生脂和生糖基因的信使RNA表达水平显著降低。高脂饲料喂养的Cyp7a1-TG小鼠增加了全身的能量消耗，并诱导了棕色脂肪组织中的脂肪酸氧化基因。这项研究表明，Cyp7a1在维持全身脂肪、血糖和能量动态平衡方面起着关键作用。随着疏水性胆汁酸库的扩大而诱导CYP7A1的表达，可能是治疗人类脂肪肝、肥胖和糖尿病等代谢疾病的潜在治疗策略。
Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the bile acid biosynthetic pathway that converts cholesterol into bile acids in the liver. Recent studies have shown that bile acids may play an important role in maintaining lipid, glucose, and energy homeostasis. However, the role of CYP7A1 in the development of obesity and diabetes is currently unclear. In this study, we demonstrated that transgenic mice overexpressing Cyp7a1 in the liver [i.e., Cyp7a1 transgenic (Cyp7a1-tg) mice] were resistant to high-fat diet (HFD)–induced obesity, fatty liver, and insulin resistance. Cyp7a1-tg mice showed increased hepatic cholesterol catabolism and an increased bile acid pool. Cyp7a1-tg mice had increased secretion of hepatic very low density lipoprotein but maintained plasma triglyceride homeostasis. Gene expression analysis showed that the hepatic messenger RNA expression levels of several critical lipogenic and gluconeogenic genes were significantly decreased in HFD-fed Cyp7a1-tg mice. HFD-fed Cyp7a1-tg mice had increased whole body energy expenditure and induction of fatty acid oxidation genes in the brown adipose tissue. This study shows that Cyp7a1 plays a critical role in maintaining whole body lipid, glucose, and energy homeostasis. The induction of CYP7A1 expression with the expansion of the hydrophobic bile acid pool may be a potential therapeutic strategy for treating metabolic disorders such as fatty liver diseases, obesity, and diabetes in humans.
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影响因子：
15.9
作者：
Watanabe, M;Houten, SM;Auwerx, J
通讯作者：
Auwerx, J
影响因子：
6.5
作者：
Gruen, ML;Plummer, MR;Hasty, AH
通讯作者：
Hasty, AH
影响因子：
8.7
作者：
Miyake, JH;Duong-Polk, XT;Davis, RA
通讯作者：
Davis, RA
影响因子：
4.8
作者：
Miyake, JH;Doung, XDT;Davis, RA
通讯作者：
Davis, RA
DOI：
10.1046/j.0014-2956.2002.02627.x
发表时间：
2002-01-01
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
Rossmeisl, M;Barbatelli, G;Kopecky, J
通讯作者：
Kopecky, J