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Hepatology ; 69(2): 817-830, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30141207

RESUMEN

Clinical conditions that result in endotoxemia, such as sepsis and alcoholic hepatitis (AH), 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, Toll-like receptor 4 (TLR4), which links to activation of nuclear factor-κB (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-kilobase (kb) deletion fragments of the ITPR3 promoter were inhibited by NF-κB subunits. Chromatin immunoprecipitation (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 those with severe AH. Conclusion: Stimulation of TLR4 by LPS activates NF-κB to down-regulate ITPR3 expression in human cholangiocytes. This may contribute to the cholestasis that can be observed in conditions such as sepsis or AH.


Asunto(s)
Conductos Biliares/efectos de los fármacos , Conductos Biliares/metabolismo , Endotoxemia/metabolismo , Endotoxinas/toxicidad , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Adulto , Señalización del Calcio/efectos de los fármacos , Colestasis/etiología , Colestasis/metabolismo , Endotoxemia/complicaciones , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Hepatitis Alcohólica/metabolismo , Humanos , Receptores de Inositol 1,4,5-Trifosfato/genética , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo
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