کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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6101077 | 1211098 | 2016 | 10 صفحه PDF | دانلود رایگان |
Background & AimsThe liver exhibits a unique capacity for regeneration in response to injury. Lymphotoxin-β receptor (LTβR), a core member of the tumor necrosis factor (TNF)/tumor necrosis factor receptor (TNFR) superfamily is known to play an important role in this process. However, the function of LTβR during pathophysiological alterations and its molecular mechanisms during liver regeneration are so far ill-characterized.MethodsLTβRâ/â mice were subjected to 70% hepatectomy and liver regeneration capacity, bile acid profiles, and transcriptome analysis were performed.ResultsLTβRâ/â deficient mice suffered from increased and prolonged liver tissue damage after 70% hepatectomy, accompanied by deregulated bile acid homeostasis. Pronounced differences in the expression patterns of genes relevant for bile acid synthesis and recirculation were observed. LTβR and TNFRp55 share downstream signalling elements. Therefore, LTβRâ/â mice were treated with etanercept to create mice functionally deficient in both signalling pathways. Strikingly, the combined blockade of TNFRp55 and LTβR signalling leads to complete failure of liver regeneration resulting in death within 24 to 48 h after PHx. Transcriptome analysis revealed a marked disparity in gene expression programs in livers of LTβRâ/â and etanercept-treated LTβRâ/â vs. wild-type animals after PHx. Murinoglobulin 2 was identified as a significantly differentially regulated gene.ConclusionsLTβR is essential for efficient liver regeneration and cooperates with TNFRp55 in this process. Differences in survival kinetics strongly suggest distinct functions for these two cytokine receptors in liver regeneration. Failure of TNFR and LTβR signalling renders liver regeneration impossible.
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Journal: Journal of Hepatology - Volume 64, Issue 5, May 2016, Pages 1108-1117