Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression.
Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression.
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DOI：
10.1002/hep.27592
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发表时间：
2015-04
期刊：
影响因子：
13.5
通讯作者：
Zhou, Huiping
中科院分区：
文献类型：
--
作者：
Nagahashi, Masayuki;Takabe, Kazuaki;Liu, Runping;Peng, Kesong;Wang, Xiang;Wang, Yun;Hait, Nitai C.;Wang, Xuan;Allegood, Jeremy C.;Yamada, Akimitsu;Aoyagi, Tomoyoshi;Liang, Jie;Pandak, William M.;Spiegel, Sarah;Hylemon, Phillip B.;Zhou, Huiping
胆汁酸已被证明是重要的激素在饲料/快速循环，使肝脏协调调节营养代谢。他们如何做到这一点还没有完全阐明。在啮齿动物肝细胞和体内，结合胆汁酸已显示通过S1 PR 2激活ERK 1/2和AKT信号通路。在这里，我们报告，喂养小鼠高脂肪饮食，牛磺胆酸钠注入到慢性胆瘘大鼠，或在小鼠肝细胞中的S1 PR 2编码基因的过表达显着上调肝SphK 2，但不是SphK 1。编码参与营养代谢的核受体/酶的关键基因在S1 PR 2 −/−和SphK 2 −/−小鼠的肝脏中显著下调。与此相反，在原代小鼠肝细胞中编码S1 PR 2的基因的过表达差异增加了SphK 2，但不是SphK 1，以及参与营养代谢的关键基因的mRNA水平。在从S1 PR 2 −/−和SphK 2 −/−小鼠制备的肝细胞中，HDAC 12的内源性抑制剂S1 P以及H3 K9、H4 K5和H2 BK 12的乙酰化的核水平显著降低。S1 PR 2 −/−和SphK 2 −/−小鼠在高脂肪饮食中迅速发展为脂肪肝，表明结合胆汁酸、S1 PR 2和SphK 2在调节肝脏脂质代谢中的重要性。
Bile acids have been shown to be important hormones during the feed/fast cycle, allowing the liver to coordinately regulate nutrient metabolism. How they accomplish this has not been fully elucidated. Conjugated bile acids have been shown to activate both the ERK1/2 and AKT signaling pathways via S1PR2 in rodent hepatocytes and in vivo. Here, we report that feeding mice a high fat diet, infusion of taurocholate into the chronic bile fistula rat, or overexpression of the gene encoding S1PR2 in mouse hepatocytes significantly up-regulated hepatic SphK2, but not SphK1. Key genes encoding nuclear receptors/enzymes involved in nutrient metabolism were significantly down-regulated in livers of S1PR2−/− and SphK2−/− mice. In contrast, overexpression of the gene encoding S1PR2 in primary mouse hepatocytes differentially increased SphK2, but not SphK1, and mRNA levels of key genes involved in nutrient metabolism. Nuclear levels of S1P, an endogenous inhibitor of HDAC 1/2, as well as the acetylation of H3K9, H4K5 and H2BK12, were significantly decreased in hepatocytes prepared from S1PR2−/− and SphK2−/− mice. Both S1PR2−/− and SphK2−/− mice rapidly developed fatty livers on a high fat diet suggesting the importance of conjugated bile acids, S1PR2 and SphK2 in regulating hepatic lipid metabolism.
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DOI：
10.1126/science.1176709
发表时间：
2009-09-04
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hait NC;Allegood J;Maceyka M;Strub GM;Harikumar KB;Singh SK;Luo C;Marmorstein R;Kordula T;Milstien S;Spiegel S
通讯作者：
Spiegel S
影响因子：
13.5
作者：
Studer, Elaine;Zhou, Xiqiao;Zhao, Renping;Wang, Yun;Takabe, Kazuaki;Nagahashi, Masayuki;Pandak, William M.;Dent, Paul;Spiegel, Sarah;Shi, Ruihua;Xu, Weiren;Liu, Xuyuan;Bohdan, Pat;Zhang, Luyong;Zhou, Huiping;Hylemon, Phillip B.
通讯作者：
Hylemon, Phillip B.
影响因子：
3.8
作者：
Almeda-Valdes, Paloma;Cuevas-Ramos, Daniel;Aguilar-Salinas, Carlos Alberto
通讯作者：
Aguilar-Salinas, Carlos Alberto
影响因子：
4.8
作者：
Takabe, Kazuaki;Kim, Roger H.;Spiegel, Sarah
通讯作者：
Spiegel, Sarah
影响因子：
13.5
作者：
HEUMAN, DM;HERNANDEZ, CR;VLAHCEVIC, ZR
通讯作者：
VLAHCEVIC, ZR