Binxia Chang1,2, Ming-Jiang Xu1, Zhou Zhou1, Yan Cai1, Man Li1, Wei Wang1, Dechun Feng1, Adeline Bertola1, Hua Wang1, George Kunos3, Bin Gao1. 1. Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD. 2. Diagnosis and Treatment Center for Non-Infectious Liver Diseases, Institute of Alcoholic Liver Disease, Beijing 302 Hospital, Beijing, People's Republic of China. 3. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
Abstract
UNLABELLED: Obesity and alcohol consumption often coexist and work synergistically to promote steatohepatitis; however, the underlying mechanisms remain obscure. Here, we demonstrate that feeding mice a high-fat diet (HFD) for as little as 3 days markedly exacerbated acute ethanol binge-induced liver neutrophil infiltration and injury. Feeding mice with an HFD for 3 months plus a single binge of ethanol induced much more severe steatohepatitis. Moreover, 3-day or 3-month HFD-plus-ethanol binge (3d-HFD+ethanol or 3m-HFD+ethanol) treatment markedly up-regulated the hepatic expression of several chemokines, including chemokine (C-X-C motif) ligand 1 (Cxcl1), which showed the highest fold (approximately 20-fold and 35-fold, respectively) induction. Serum CXCL1 protein levels were also markedly elevated after the HFD+ethanol treatment. Blockade of CXCL1 with a CXCL1 neutralizing antibody or genetic deletion of the Cxcl1 gene reduced the HFD+ethanol-induced hepatic neutrophil infiltration and injury, whereas overexpression of Cxcl1 exacerbated steatohepatitis in HFD-fed mice. Furthermore, expression of Cxcl1 messenger RNA was up-regulated in hepatocytes, hepatic stellate cells, and endothelial cells isolated from HFD+ethanol-fed mice compared to mice that were only given the HFD, with the highest fold induction observed in hepatocytes. In vitro stimulation of hepatocytes with palmitic acid up-regulated the expression of Cxcl1 messenger RNA, and this up-regulation was attenuated after treatment with an inhibitor of extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, or nuclear factor κB. In addition, hepatic or serum levels of free fatty acids were higher in HFD+ethanol-fed mice than in the control groups. CONCLUSION: An HFD combined with acute ethanol consumption synergistically induces acute liver inflammation and injury through the elevation of hepatic or serum free fatty acids and subsequent up-regulation of hepatic CXCL1 expression and promotion of hepatic neutrophil infiltration. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
UNLABELLED: Obesity and alcohol consumption often coexist and work synergistically to promote steatohepatitis; however, the underlying mechanisms remain obscure. Here, we demonstrate that feeding mice a high-fat diet (HFD) for as little as 3 days markedly exacerbated acute ethanol binge-induced liver neutrophil infiltration and injury. Feeding mice with an HFD for 3 months plus a single binge of ethanol induced much more severe steatohepatitis. Moreover, 3-day or 3-month HFD-plus-ethanol binge (3d-HFD+ethanol or 3m-HFD+ethanol) treatment markedly up-regulated the hepatic expression of several chemokines, including chemokine (C-X-C motif) ligand 1 (Cxcl1), which showed the highest fold (approximately 20-fold and 35-fold, respectively) induction. Serum CXCL1 protein levels were also markedly elevated after the HFD+ethanol treatment. Blockade of CXCL1 with a CXCL1 neutralizing antibody or genetic deletion of the Cxcl1 gene reduced the HFD+ethanol-induced hepatic neutrophil infiltration and injury, whereas overexpression of Cxcl1 exacerbated steatohepatitis in HFD-fed mice. Furthermore, expression of Cxcl1 messenger RNA was up-regulated in hepatocytes, hepatic stellate cells, and endothelial cells isolated from HFD+ethanol-fed mice compared to mice that were only given the HFD, with the highest fold induction observed in hepatocytes. In vitro stimulation of hepatocytes with palmitic acid up-regulated the expression of Cxcl1 messenger RNA, and this up-regulation was attenuated after treatment with an inhibitor of extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase, or nuclear factor κB. In addition, hepatic or serum levels of free fatty acids were higher in HFD+ethanol-fed mice than in the control groups. CONCLUSION: An HFD combined with acute ethanol consumption synergistically induces acute liver inflammation and injury through the elevation of hepatic or serum free fatty acids and subsequent up-regulation of hepatic CXCL1 expression and promotion of hepatic neutrophil infiltration. Published 2015. This article is a U.S. Government work and is in the public domain in the USA.
Authors: C David Williams; Mary Lynn Bajt; Matthew R Sharpe; Mitchell R McGill; Anwar Farhood; Hartmut Jaeschke Journal: Toxicol Appl Pharmacol Date: 2014-01-15 Impact factor: 4.219
Authors: Sandra J Campbell; Paula M Hughes; John P Iredale; David C Wilcockson; Sara Waters; Fabian Docagne; V Hugh Perry; Daniel C Anthony Journal: FASEB J Date: 2003-04-22 Impact factor: 5.191
Authors: Thiyagarajan Gopal; Narendra Kumar; Curtis Perriotte-Olson; Carol A Casey; Terrence M Donohue; Edward N Harris; Geoffrey Talmon; Alexander V Kabanov; Viswanathan Saraswathi Journal: Am J Physiol Gastrointest Liver Physiol Date: 2020-01-13 Impact factor: 4.052
Authors: Yan Cai; Ming-Jiang Xu; Erik H Koritzinsky; Zhou Zhou; Wei Wang; Haixia Cao; Peter St Yuen; Ruth A Ross; Robert A Star; Suthat Liangpunsakul; Bin Gao Journal: JCI Insight Date: 2017-07-20