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• W2029754162 abstract "Background/AimsIn sepsis-associated cholestasis, expression of many genes involved in bile acid transport, including Ntcp, is suppressed by cytokines. Kupffer cells (KC) are an important source of cytokines in sepsis. To assess the consequences of KC depletion on hepatic Ntcp expression in endotoxemic rats.MethodsSprague–Dawley rats received liposomal clodronate (CLO) or vehicle (PBS) to deplete KC prior to lipopolysaccharide (LPS) exposure. Plasma and liver samples were taken 1 and 16 h after LPS exposure.ResultsComplete CLO-depletion of KC by was demonstrated by immunohistochemistry. Hepatic gene expression of IL-1β and TNFα as well as TNFα plasma levels in CLO/LPS-injected animals were significantly reduced to a mean of 41, 36 and 23% of controls injected with LPS only. Ntcp RNA- and protein expression was significantly higher whereas plasma bile salt concentration was lower in CLO/LPS animals vs. animals injected with LPS only. Binding activity of transcription factors RXR:RAR and HNF1α was decreased in LPS only controls but preserved in CLO/LPS treated animals.ConclusionsClodronate-depletion of KC blocks cytokine-mediated Ntcp suppression upon endotoxin exposure. KC may represent pharmacological targets for treatment of sepsis-associated cholestasis. In sepsis-associated cholestasis, expression of many genes involved in bile acid transport, including Ntcp, is suppressed by cytokines. Kupffer cells (KC) are an important source of cytokines in sepsis. To assess the consequences of KC depletion on hepatic Ntcp expression in endotoxemic rats. Sprague–Dawley rats received liposomal clodronate (CLO) or vehicle (PBS) to deplete KC prior to lipopolysaccharide (LPS) exposure. Plasma and liver samples were taken 1 and 16 h after LPS exposure. Complete CLO-depletion of KC by was demonstrated by immunohistochemistry. Hepatic gene expression of IL-1β and TNFα as well as TNFα plasma levels in CLO/LPS-injected animals were significantly reduced to a mean of 41, 36 and 23% of controls injected with LPS only. Ntcp RNA- and protein expression was significantly higher whereas plasma bile salt concentration was lower in CLO/LPS animals vs. animals injected with LPS only. Binding activity of transcription factors RXR:RAR and HNF1α was decreased in LPS only controls but preserved in CLO/LPS treated animals. Clodronate-depletion of KC blocks cytokine-mediated Ntcp suppression upon endotoxin exposure. KC may represent pharmacological targets for treatment of sepsis-associated cholestasis." @default.
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• W2029754162 date "2005-01-01" @default.
• W2029754162 modified "2023-10-18" @default.
• W2029754162 title "Kupffer cell depletion with liposomal clodronate prevents suppression of Ntcp expression in endotoxin-treated rats" @default.
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• W2029754162 doi "https://doi.org/10.1016/j.jhep.2004.09.019" @default.
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