Blockade of CXCR3 using CXCR3 antagonists in mice reversed the established steatohepatitis.ĬXCR3 plays a pivotal role in NASH development by inducing production of cytokines, macrophage infiltration, fatty acid synthesis and causing autophagy deficiency and ER stress.Īnimal model Autophagy CXCR3 Macrophage Non-alcoholic steatohepatitis.Ĭopyright © 2015 European Association for the Study of the Liver. Inhibition of CXCR3 using CXCR3 antagonist significantly suppressed MCD-induced steatosis and hepatocytes injury in AML-12 hepatocytes. 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. CXCR3 was also linked to steatosis through inducing hepatic lipogenic genes.
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). Compared with WT littermates, CXCR3(-/-) mice were more resistant to both MCD and HFHC diet-induced steatohepatitis. In addition, MCD-fed WT mice were administrated with CXCR3 specific antagonists.ĬXCR3 was significantly upregulated in liver tissues of patients with NAFLD and in dietary-induced NASH animal models. 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. Human liver tissues were obtained from 24 non-alcoholic fatty liver disease (NAFLD) patients and 20 control subjects. We aimed to investigate the role of CXCR3 in NASH. However, the role of CXCR3 in non-alcoholic steatohepatitis (NASH) remains unclear. Electronic address: & aims:ĬXC chemokine receptor 3 (CXCR3) is involved in virus-related chronic liver inflammation. 6 Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.5 Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China.4 Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.3 Department of Surgery, LKS Faculty of Medicine, University of Hong Kong, Hong Kong.2 Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong Institute of Liver Disease, Beijing Military General Hospital, Beijing, China.1 Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK-Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
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