Effects of Endotoxin on Type 3 Inositol 1,4,5-Trisphosphate Receptor in Human Cholangiocytes

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Andressa FrancaMichael H Nathanson

Abstract

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 b...Continue Reading

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Citations

Jun 30, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Pimwipa UeasilamongkolJittima Weerachayaphorn
Dec 6, 2019·World Journal of Gastroenterology : WJG·Fernanda de Oliveira LemosM Fatima Leite
Dec 20, 2018·International Journal of Molecular Sciences·Michele Angela RodriguesMichael Harris Nathanson
Nov 23, 2020·Alcoholism, Clinical and Experimental Research·Charles Ho, Chin-Yo Lin
Feb 13, 2021·Journal of Experimental & Clinical Cancer Research : CR·Mengzhao ZhangJinhai Fan
Mar 23, 2021·FEBS Letters·Chaonan JinJean-François Dufour
Dec 23, 2021·Food & Function·Li-Yang WeiYing Chen

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