title: CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of non-alcoholic steatohepatitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Gastrointestinal Cancer Biology and Therapeutics Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Gastrointestinal Cancer Biology and Therapeutics Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Jiayun
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Kwan
authors.initials: K
authors.lastname: Man
authors.affiliation: Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Gastrointestinal Cancer Biology and Therapeutics Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Eagle S H
authors.initials: ES
authors.lastname: Chu
authors.affiliation: Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Gastrointestinal Cancer Biology and Therapeutics Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Tung On
authors.initials: TO
authors.lastname: Yau
authors.affiliation: Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Joanne C Y
authors.initials: JC
authors.lastname: Sung
authors.affiliation: Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Minnie Y Y
authors.initials: MY
authors.lastname: Go
authors.affiliation: Department of Pathology and Center of Infection and Immunology, The University of Hong Kong, Hong Kong, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Deng
authors.affiliation: Department of Pathology and Center of Infection and Immunology, The University of Hong Kong, Hong Kong, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Lu
authors.affiliation: Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Vincent W S
authors.initials: VW
authors.lastname: Wong
authors.affiliation: Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Gastrointestinal Cancer Biology and Therapeutics Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.
authors.forename: Joseph J Y
authors.initials: JJ
authors.lastname: Sung
authors.affiliation: Australian National University Medical School at The Canberra Hospital, Canberra, Australia.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Farrell
authors.affiliation: Institute of Digestive Disease and The Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China; Gastrointestinal Cancer Biology and Therapeutics Laboratory, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China. Electronic address: junyu@cuhk.edu.hk.
authors.forename: Jun
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D015415:Biomarkers; D054357:Chemokine CXCL10; C485433:Cxcl10 protein, mouse; D016207:Cytokines; D016328:NF-kappa B
keywords: Animal model; Biomarker; Chemokine; Inflammation; Non-alcoholic fatty liver disease