title: Short- or long-term high-fat diet feeding plus acute ethanol binge synergistically induce acute liver injury in mice: an important role for CXCL1.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.|Diagnosis and Treatment Center for Non-Infectious Liver Diseases, Institute of Alcoholic Liver Disease, Beijing 302 Hospital, Beijing, People's Republic of China.
authors.forename: Binxia
authors.initials: B
authors.lastname: Chang
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.
authors.forename: Dechun
authors.initials: D
authors.lastname: Feng
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.
authors.forename: Adeline
authors.initials: A
authors.lastname: Bertola
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.affiliation: Laboratory of Liver Diseases and the, National Institutes of Health, Bethesda, MD.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000208:Acute Disease; D000818:Animals; D063425:Binge Drinking / Q000150:complications*; D054360:Chemokine CXCL1 / Q000502:physiology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D000431:Ethanol / Q000008:administration & dosage*; D005234:Fatty Liver / Q000209:etiology; D008107:Liver Diseases / Q000209:etiology* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D013997:Time Factors
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D000431:Ethanol