INTRACELLULAR SIGNALING BY BILE ACIDS.
INTRACELLULAR SIGNALING BY BILE ACIDS.
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胆汁酸的细胞内信号传导。
DOI：
10.3329/jbs.v20i0.17647
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Anwer MS
中科院分区：
文献类型：
--
作者：
Anwer MS
胆汁酸是由胆固醇合成的，它对肝脏既有益又有害。有益作用包括胆汁分泌、免疫调节、细胞存活，而毒性作用包括胆汁淤积、细胞凋亡和细胞毒性。人们认为胆汁酸通过激活细胞内信号通路产生许多这些作用。然而，将细胞内信号传导与胆汁酸的特异性和有时相反的作用联系起来一直是一个挑战。越来越明显的是，胆汁酸通过激活磷酸肌肽3激酶（PI3K）、蛋白激酶Cs （PKCs）和丝裂原活化蛋白激酶（MAPK）的不同异构体产生不同的作用。因此，胆汁酸的凋亡作用可能是通过PI3K-110γ介导的，而cAMP-GEF途径诱导的细胞保护作用涉及PI3K-p110α/β亚型的激活。非典型PKCζ可能介导有益作用，而nPKCε可能介导毒性作用，而cPKCα和nPKCδ可能同时参与胆汁酸的有益和毒性作用。nPKCδ活化的相反作用可能取决于nPKCδ磷酸化位点。激活ERK1/2和JNK1/2通路似乎分别介导胆汁酸的有益和毒性作用。激活p38α MAPK和p38β MAPK可能分别介导胆汁酸的促胆和阻胆作用。未来的研究阐明了同种异构体对胆汁形成的特异性影响，这将使我们能够确定治疗胆汁淤积症的潜在治疗靶点。
Bile acids, synthesized from cholesterol, are known to produce beneficial as well as toxic effects in the liver. The beneficial effects include choleresis, immunomodulation, cell survival, while the toxic effects include cholestasis, apoptosis and cellular toxicity. It is believed that bile acids produce many of these effects by activating intracellular signaling pathways. However, it has been a challenge to relate intracellular signaling to specific and at times opposing effects of bile acids. It is becoming evident that bile acids produce different effects by activating different isoforms of phosphoinositide 3-kinase (PI3K), Protein kinase Cs (PKCs), and mitogen activated protein kinases (MAPK). Thus, the apoptotic effect of bile acids may be mediated via PI3K-110γ, while cytoprotection induce by cAMP-GEF pathway involves activation of PI3K-p110α/β isoforms. Atypical PKCζ may mediate beneficial effects and nPKCε may mediate toxic effects, while cPKCα and nPKCδ may be involved in both beneficial and toxic effects of bile acids. The opposing effects of nPKCδ activation may depend on nPKCδ phosphorylation site(s). Activation of ERK1/2 and JNK1/2 pathway appears to mediate beneficial and toxic effects, respectively, of bile acids. Activation of p38α MAPK and p38β MAPK may mediate choleretic and cholestatic effects, respectively, of bile acids. Future studies clarifying the isoform specific effects on bile formation should allow us to define potential therapeutic targets in the treatment of cholestatic disorders.