Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes.
Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes.
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DOI：
10.1002/hep.24681
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发表时间：
2012-01
期刊：
影响因子：
13.5
通讯作者：
Hylemon, Phillip B.
中科院分区：
文献类型：
--
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.
胆汁酸已被证明是肝脏和胃肠道细胞的重要调节分子。它们可以激活各种细胞信号传导途径，包括细胞外调节激酶（ERK）1/2和AKT以及G蛋白偶联受体（GPCR）、TGR 5/M-BAR。在原代啮齿类动物肝细胞中，结合胆汁酸激活ERK 1/2和AKT信号通路对百日咳毒素（PTX）和显性阴性Gαi敏感。然而，负责激活这些途径的GPCR尚未确定。筛选HEK 293细胞中表达的脂质激活系统发育家族中的GPCR，鉴定出鞘氨醇1-磷酸受体2（S1 P2）被牛磺胆酸盐（TCA）激活。在原代大鼠肝细胞中，TCA、牛磺脱氧胆酸（TDCA）、牛磺熊脱氧胆酸（TUDCA）、甘氨胆酸（GCA）、甘氨脱氧胆酸（GDCA）和S1 P诱导的ERK 1/2和AKT活化可被S1 P2拮抗剂JTE-013显著抑制。JTE-013显著抑制慢性胆瘘大鼠肝脏ERK 1/2和AKT活化以及TCA诱导的短异源二聚体伴侣（SHP）mRNA。用编码S1 P2 shRNA的重组慢病毒敲低S1 P2的表达，可显著抑制TCA和S1 P对原代大鼠肝细胞ERK 1/2和AKT的激活。从S1 P2基因敲除（S1 P2 −/−）小鼠制备的原代肝细胞在TCA激活ERK 1/2和AKT通路时显著钝化。S1 P受体的结构建模表明，只有S1 P2可以容纳TCA结合。总之，所有这些数据支持以下假设：结合胆汁酸主要通过S1 P2激活原代啮齿动物肝细胞中的ERK 1/2和AKT信号通路。
Bile acids have been shown to be important regulatory molecules for cells in the liver and gastrointestinal tract. They can activate various cell signaling pathways including the extracellular regulated kinase (ERK)1/2 and AKT as well as the G-protein coupled receptor (GPCR), TGR5/M-BAR. Activation of the ERK1/2 and AKT signaling pathways by conjugated bile acids has been reported to be pertussis toxin (PTX) and dominant negative Gαi sensitive in primary rodent hepatocytes. However, the GPCRs responsible for activation of these pathways have not been identified. Screening GPCRs in the lipid activated phylogenetic family, expressed in HEK293 cells, identified sphingosine 1-phosphate receptor 2 (S1P2) as being activated by taurocholate (TCA). TCA, taurodeoxycholic acid (TDCA), tauroursodeoxycholic acid (TUDCA), glycocholic acid (GCA), glycodeoxycholic acid (GDCA), and S1P-induced activation of ERK1/2 and AKT were significantly inhibited by JTE-013, a S1P2 antagonist, in primary rat hepatocytes. JTE-013 significantly inhibited hepatic ERK1/2 and AKT activation as well as short heterodimeric partner (SHP) mRNA induction by TCA in the chronic bile fistula rat. Knock down of the expression of S1P2 by a recombinant lentivirus encoding S1P2 shRNA, markedly inhibited the activation of ERK1/2 and AKT by TCA and S1P in rat primary hepatocytes. Primary hepatocytes prepared from S1P2 knock out (S1P2−/−) mice were significantly blunted in the activation of the ERK1/2 and AKT pathways by TCA. Structural modeling of the S1P receptors indicated that only S1P2 can accommodate TCA binding. In summary, all these data support the hypothesis that conjugated bile acids activate the ERK1/2 and AKT signaling pathways primarily via S1P2 in primary rodent hepatocytes.
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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：
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影响因子：
13.5
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影响因子：
4.8
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DOI：
10.1016/s0006-291x(02)02550-0
发表时间：
2002-11-15
影响因子：
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作者：
Maruyama, T;Miyamoto, Y;Tanaka, K
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