Effects of Endotoxin on Type 3 Inositol 1,4,5-Trisphosphate Receptor in Human Cholangiocytes.
Effects of Endotoxin on Type 3 Inositol 1,4,5-Trisphosphate Receptor in Human Cholangiocytes.
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DOI：
10.1002/hep.30228
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Nathanson MH
中科院分区：
文献类型：
--
作者：
Franca A;Carlos Melo Lima Filho A;Guerra MT;Weerachayaphorn J;Loiola Dos Santos M;Njei B;Robert M;Xavier Lima C;Vieira Teixeira Vidigal P;Banales JM;Ananthanarayanam M;Leite MF;Nathanson MH
导致内毒素血症的临床状况，如败血症和酒精性肝炎，通常伴有胆汁淤积。虽然肝细胞对脂多糖（LPS）反应的变化已得到很好的表征，但对胆管细胞是否以及如何促成这种形式的胆汁淤积知之甚少。我们研究了内毒素对3型三磷酸肌醇受体（ITPR 3）的表达和功能的影响，因为这是胆管细胞中主要的细胞内Ca 2+释放通道，它的丧失会损害小管碳酸氢盐的分泌。胆管细胞表达LPS受体TLR 4，TLR 4与NF-κB活化有关。对人ITPR 3启动子的分析揭示了对NF-κB的5个假定的反应元件，并且启动子活性被p65/p50抑制。NF-κB亚基可抑制ITPR 3启动子的0.5和1.0 kb缺失片段。ChIP分析显示NF-κB与ITPR 3启动子相互作用，并伴随H3 K9甲基化的增加。LPS可降低胆管细胞ITPR 3 mRNA和蛋白的表达，并降低胆管细胞对钙激动剂刺激的敏感性。这种减少被TLR 4的抑制逆转。ITPR 3表达减少或缺乏胆汁淤积脓毒症患者和严重酒精性肝炎患者的胆管细胞。LPS刺激TLR 4激活NF-κB下调人胆管细胞ITPR 3表达这可能有助于胆汁淤积，可以在败血症或酒精性肝炎等疾病中观察到。
Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis, often are accompanied by cholestasis. Although hepatocellular changes in response to lipopolysaccharide (LPS) have been well characterized, less is known about whether and how cholangiocytes contribute to this form of cholestasis. We examined effects of endotoxin on expression and function of the type 3 inositol trisphosphate receptor (ITPR3), because this is the main intracellular Ca2+ release channel in cholangiocytes, and loss of it impairs ductular bicarbonate secretion. Bile duct cells expressed the LPS receptor TLR4, which links to activation of NF-κB. Analysis of the human ITPR3 promoter revealed five putative response elements to NF-κB, and promoter activity was inhibited by p65/p50. Nested 0.5 and 1.0 kb deletion fragments of the ITPR3 promoter were inhibited by NF-κB subunits. ChIP assay showed that NF-κB interacts with the ITPR3 promoter, with an associated increase in H3K9 methylation. LPS decreased ITPR3 mRNA and protein expression, and also decreased sensitivity of bile duct cells to calcium agonist stimuli. This reduction was reversed by inhibition of TLR4. ITPR3 expression was decreased or absent in cholangiocytes from patients with cholestasis of sepsis and from patients with severe alcoholic hepatitis. Stimulation of TLR4 via LPS activates NF-κB to downregulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or alcoholic hepatitis.
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影响因子：
64.8
作者：
Kuchay S;Giorgi C;Simoneschi D;Pagan J;Missiroli S;Saraf A;Florens L;Washburn MP;Collazo-Lorduy A;Castillo-Martin M;Cordon-Cardo C;Sebti SM;Pinton P;Pagano M
通讯作者：
Pagano M
影响因子：
13.5
作者：
Cruz, Laura N.;Guerra, Mateus T.;Kruglov, Emma;Mennone, Albert;Garcia, Celia R. S.;Chen, Ju;Nathanson, Michael H.
通讯作者：
Nathanson, Michael H.
影响因子：
4.4
作者：
Braconi C;Patel T
通讯作者：
Patel T
影响因子：
29.4
作者：
Hirata, K;Nathanson, MH
通讯作者：
Nathanson, MH
影响因子：
24.5
作者：
Blaya, Delia;Coll, Mar;Sancho-Bru, Pau
通讯作者：
Sancho-Bru, Pau