CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy

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• 作者：Xiang Zhang¹ ; Juqiang Han¹ ; ² ; Kwan Man³ ; Xiaoxing Li¹ ; ⁴ ; Jinghua Du¹ ; ⁵ ; Eagle S.H. Chu¹ ; Minnie Y.Y. Go¹ ; Joseph J.Y. Sung¹ ; Jun Yu¹ ; ^{junyu@cuhk.edu.hk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CXCR3 ; CXC chemokine receptor 3 ; NASH ; non-alcoholic steatohepatitis ; NAFLD ; non-alcoholic fatty liver disease ; CXCR3&minus ; /&minus ; CXCR3 knockout ; WT ; wild-type ; MCD ; methionine-and-choline-deficient ; HFHC ; high-fat high-carbohydrate high-cholesterol ; ER ; endoplasmic reticulum ; TNF-α ; tumor necrosis factor alpha ; MCP-1 ; monocyte chemoattractant protein 1 ; IL ; interleukin ; ICAM-1 ; intercellular adhesion molecule-1 ; LXR ; liver X receptors ; SREBP-1c ; sterol regulatory element binding protein iso
• 刊名：Journal of Hepatology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：64
• 期：1
• 页码：160-170
• 全文大小：3827 K

文摘

CXC chemokine receptor 3 (CXCR3) is involved in virus-related chronic liver inflammation. However, the role of CXCR3 in non-alcoholic steatohepatitis (NASH) remains unclear. We aimed to investigate the role of CXCR3 in NASH.

Methods

Human liver tissues were obtained from 24 non-alcoholic fatty liver disease (NAFLD) patients and 20 control subjects. CXCR3 knockout (CXCR3^−/−), obese db/db mice and their wild-type (WT) littermates were used in both methionine-and-choline-deficient (MCD) diet and high-fat high-carbohydrate high-cholesterol (HFHC) diet-induced NASH models. In addition, MCD-fed WT mice were administrated with CXCR3 specific antagonists.

Results

CXCR3 was significantly upregulated in liver tissues of patients with NAFLD and in dietary-induced NASH animal models. Compared with WT littermates, CXCR3^−/− mice were more resistant to both MCD and HFHC diet-induced steatohepatitis. Induction of CXCR3 in dietary-induced steatohepatitis was associated with the increased expression of hepatic pro-inflammatory cytokines, activation of NF-κB, macrophage infiltration and T lymphocytes accumulation (Th1 and Th17 immune response). CXCR3 was also linked to steatosis through inducing hepatic lipogenic genes. Moreover, CXCR3 is associated with autophagosome-lysosome impairment and endoplasmic reticulum (ER) stress in steatohepatitis as evidenced by LC3-II and p62/SQSTM1 accumulation and the induction of GRP78, phospho-PERK and phospho-eIF2α. Inhibition of CXCR3 using CXCR3 antagonist significantly suppressed MCD-induced steatosis and hepatocytes injury in AML-12 hepatocytes. Blockade of CXCR3 using CXCR3 antagonists in mice reversed the established steatohepatitis.

Conclusions

CXCR3 plays a pivotal role in NASH development by inducing production of cytokines, macrophage infiltration, fatty acid synthesis and causing autophagy deficiency and ER stress.