CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of non-alcoholic steatohepatitis
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摘要Background & Aims Perpetuate liver inflammation is crucial in the pathogenesis of non-alcoholic steatohepatitis (NASH). Expression of CXCL10, a pro-inflammatory cytokine, correlates positively with obesity and type 2 diabetes. Whether CXCL10 plays a role in NASH was unknown. We aimed to investigate the functional and clinical impact of CXCL10 in NASH. Methods Cxcl10 gene-deleted (Cxcl10-/-) and C57BL/6 wild type (WT) mice were fed a methionine- and choline-deficient (MCD) diet for 4 or 8 weeks. In other experiments, we injected neutralizing anti-CXCL10 mAb into MCD-fed WT mice. Human serum was obtained from 147 patients with biopsy-proven non-alcoholic fatty liver disease and 73 control subjects. Results WT mice, fed the MCD diet, developed steatohepatitis with higher hepatic CXCL10 expression. Cxcl10-/- mice were refractory to MCD-induced steatohepatitis. We further revealed that CXCL10 was associated with the induction of important pro-inflammatory cytokines (TNF-α, IL-1β, and MCP-1) and activation of the NF-κB pathway. CXCL10 was linked to steatosis through upregulation of the lipogenic factors SREBP-1c and LXR, and also to oxidative stress (upregulation of CYP2E1 and C/EBPβ). Blockade of CXCL10 protected against hepatocyte injury in vitro and against steatohepatitis development in mice. We further investigated the clinical impact of CXCL10 and found circulating and hepatic CXCL10 levels were significantly higher in human NASH. Importantly, the circulating CXCL10 level was correlated with the degree of lobular inflammation and was an independent risk factor for NASH patients. Conclusions We demonstrate for the first time that CXCL10 plays a pivotal role in the pathogenesis of experimental steatohepatitis. CXCL10 maybe a potential non-invasive biomarker for NASH patients.
著者Zhang X., Shen J., Man K., Chu E.S.H., Yau T.O., Sung J.C.Y., Go M.Y.Y., Deng J., Lu L., Wong V.W.S., Sung J.J.Y., Farrell G., Yu J.
期刊名稱Journal of Hepatology
出版年份2014
月份1
日期1
卷號61
期次6
出版社Elsevier BV
出版地Netherlands
頁次1365 - 1375
國際標準期刊號0168-8278
電子國際標準期刊號1600-0641
語言英式英語
關鍵詞Animal model, Biomarker, Chemokine, Inflammation, Non-alcoholic fatty liver disease

上次更新時間 2020-28-10 於 03:00