Regulation of cholesterol and bile acid homeostasis by the cholesterol 7α-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice.
Regulation of cholesterol and bile acid homeostasis by the cholesterol 7α-hydroxylase/steroid response element-binding protein 2/microRNA-33a axis in mice.
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DOI：
10.1002/hep.26427
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发表时间：
2013-09
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;Francl, Jessica M.;Boehme, Shannon;Chiang, John Y. L.
胆汁酸合成不仅产生肠道营养吸收所需的生理洗涤剂，而且在调节肝脏和全身代谢稳态中起关键作用。我们最近报道，肝脏中胆固醇7α-羟化酶（CYP 7A 1）的过表达导致Cyp 7a 1转基因（Cyp 7a 1-tg）小鼠中代谢稳态的改善（Li等人，Hepatology 2010; 52：678-690 & Li等人，Hepatology 2011; 53：996-1006）。本研究进一步探讨了胆汁酸代谢和脂质稳态之间的分子联系。微阵列基因分析显示，CYP 7A 1过表达导致显着激活类固醇反应元件结合蛋白2（SREBP 2）调节的胆固醇代谢网络和不存在胆汁酸抑制脂肪生成基因表达的Cyp 7a 1-tg小鼠的肝脏。有趣的是，Cyp 7a 1-tg小鼠表现出显著升高的肝胆固醇合成率，但降低肝脂肪酸合成率，这是伴随着增加的14 C-葡萄糖衍生的乙酰辅酶A掺入固醇粪便排泄。SREBP 2的诱导也共诱导Cyp 7a 1-tg小鼠中SREBP 2基因中的内含子microRNA-33 a（miR-33 a）。小鼠肝脏中miR-33 a的过表达导致胆汁酸库减少、肝脏胆固醇含量增加和血清胆固醇降低。这项研究表明，CYP 7A 1-SREBP 2-miR-33 a轴在调节肝脏胆固醇、胆汁酸和脂肪酸合成中起关键作用。miR-33 a的拮抗作用可能是增加胆汁酸合成以维持脂质稳态并预防非酒精性脂肪性肝病（NAFLD）、糖尿病和肥胖的潜在策略。
Bile acid synthesis not only produces physiological detergents required for intestinal nutrient absorption, but also plays a critical role in regulating hepatic and whole body metabolic homeostasis. We recently reported that over-expression of cholesterol 7α-hydroxylase (CYP7A1) in the liver resulted in improved metabolic homeostasis in Cyp7a1 transgenic (Cyp7a1-tg) mice (Li et al., Hepatology 2010; 52:678-690 & Li et al., Hepatology 2011; 53:996–1006). This study further investigated the molecular links between bile acid metabolism and lipid homeostasis. Microarray gene profiling revealed that CYP7A1 overexpression led to marked activation of the steroid response element binding protein 2 (SREBP2)-regulated cholesterol metabolic network and absence of bile acid repression of lipogenic gene expression in the liver of Cyp7a1-tg mice. Interestingly, Cyp7a1-tg mice showed significantly elevated hepatic cholesterol synthesis rates but reduced hepatic fatty acid synthesis rates, which was accompanied by increased 14C-glucose-derived acetyl-CoA incorporation into sterols for fecal excretion. Induction of SREBP2 also co-induces intronic microRNA-33a (miR-33a) in the SREBP2 gene in Cyp7a1-tg mice. Overexpression of miR-33a in the liver resulted in decreased bile acid pool, increased hepatic cholesterol content and lowered serum cholesterol in mice. This study suggests that a CYP7A1-SREBP2-miR-33a axis plays a critical role in regulation of hepatic cholesterol, bile acid and fatty acid synthesis. Antagonism of miR-33a may be a potential strategy to increase bile acid synthesis to maintain lipid homeostasis and prevent non-alcoholic fatty liver disease (NAFLD), diabetes and obesity.
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DOI：
10.1038/oby.2009.102
发表时间：
2009-09
期刊：
Obesity (Silver Spring, Md.)
影响因子：
--
作者：
Patti ME;Houten SM;Bianco AC;Bernier R;Larsen PR;Holst JJ;Badman MK;Maratos-Flier E;Mun EC;Pihlajamaki J;Auwerx J;Goldfine AB
通讯作者：
Goldfine AB
DOI：
10.1126/science.1189123
发表时间：
2010-06-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Najafi-Shoushtari SH;Kristo F;Li Y;Shioda T;Cohen DE;Gerszten RE;Näär AM
通讯作者：
Näär AM
影响因子：
4.8
作者：
Gerin, Isabelle;Clerbaux, Laure-Alix;Bommer, Guido T.
通讯作者：
Bommer, Guido T.
影响因子：
9.9
作者：
Shaham, Oded;Wei, Ru;Wang, Thomas J.;Ricciardi, Catherine;Lewis, Gregory D.;Vasan, Ramachandran S.;Carr, Steven A.;Thadhani, Ravi;Gerszten, Robert E.;Mootha, Vamsi K.
通讯作者：
Mootha, Vamsi K.
影响因子：
2.9
作者：
Simonen, M.;Dali-Youcef, N.;Kaminska, D.;Venesmaa, S.;Kakela, P.;Paakkonen, M.;Hallikainen, M.;Kolehmainen, M.;Uusitupa, M.;Moilanen, L.;Laakso, M.;Gylling, H.;Patti, M. E.;Auwerx, J.;Pihlajamaki, Jussi
通讯作者：
Pihlajamaki, Jussi