Xiang Zhang1, Jiayun Shen1, Kwan Man2, Eagle S H Chu1, Tung On Yau1, Joanne C Y Sung3, Minnie Y Y Go3, Jun Deng4, Liwei Lu4, Vincent W S Wong3, Joseph J Y Sung1, Geoffrey Farrell5, Jun Yu6. 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, 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. 2. Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China. 3. 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. 4. Department of Pathology and Center of Infection and Immunology, The University of Hong Kong, Hong Kong, China. 5. Australian National University Medical School at The Canberra Hospital, Canberra, Australia. 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, 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.
Abstract
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.
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.
Authors: Joel T Haas; Luisa Vonghia; Denis A Mogilenko; An Verrijken; Olivier Molendi-Coste; Sébastien Fleury; Audrey Deprince; Artemii Nikitin; Eloïse Woitrain; Lucie Ducrocq-Geoffroy; Samuel Pic; Bruno Derudas; Hélène Dehondt; Céline Gheeraert; Luc Van Gaal; Ann Driessen; Philippe Lefebvre; Bart Staels; Sven Francque; David Dombrowicz Journal: Nat Metab Date: 2019-06-14
Authors: Ryan E Feaver; Banumathi K Cole; Mark J Lawson; Stephen A Hoang; Svetlana Marukian; Brett R Blackman; Robert A Figler; Arun J Sanyal; Brian R Wamhoff; Ajit Dash Journal: JCI Insight Date: 2016-12-08
Authors: Samar H Ibrahim; Petra Hirsova; Kyoko Tomita; Steven F Bronk; Nathan W Werneburg; Stephen A Harrison; Val S Goodfellow; Harmeet Malhi; Gregory J Gores Journal: Hepatology Date: 2015-12-11 Impact factor: 17.425