title: Chronic Alcohol Consumption Causes Liver Injury in High-Fructose-Fed Male Mice Through Enhanced Hepatic Inflammatory Response.
abstract: BACKGROUND
  Obesity and the metabolic syndrome occur in approximately one-third of patients with alcoholic liver disease (ALD). The increased consumption of fructose parallels the increased prevalence of obesity and the metabolic syndrome in the United States and worldwide. In this study, we investigated whether dietary high fructose potentiates chronic alcohol-induced liver injury, and explored potential mechanism(s).
  
  
  METHODS
  Six-week-old male C57BL/6J mice were assigned to 4 groups: control, high fructose, chronic ethanol (EtOH), and high fructose plus chronic alcohol. The mice were fed either control diet or high-fructose diet (60%, w/w) for 18 weeks. Chronic alcohol-fed mice were given 20% (v/v) ethanol (Meadows-Cook model) ad libitum as the only available liquid from the 9th week through the 18th week. Liver injury, steatosis, hepatic inflammatory gene expression, and copper status were assessed.
  
  
  RESULTS
  High-fructose diet and chronic alcohol consumption alone each induce hepatic fat accumulation and impair copper status. However, the combination of dietary high fructose plus chronic alcohol synergistically induced liver injury as evidenced by robustly increased plasma alanine aminotransferase and aspartate aminotransferase, but the combination did not exacerbate hepatic fat accumulation nor worsen copper status. Moreover, FE-fed mice were characterized by prominent microvesicular steatosis. High-fructose diet and chronic alcohol ingestion together led to a significant up-regulation of Kupffer cell (KC) M1 phenotype gene expression (e.g., tumor necrosis factor-α and monocyte chemoattractant protein-1), as well as Toll-like receptor 4 (TLR4) signaling gene expression, which is also associated with the up-regulation of KCs and activation marker gene expression, including Emr1, CD68, and CD163.
  
  
  CONCLUSIONS
  Our data suggest that dietary high fructose may potentiate chronic alcohol consumption-induced liver injury. The underlying mechanism might be due to the synergistic effect of dietary high fructose and alcohol on the activation of the TLR4 signaling pathway, which in turn leads to KC activation and phenotype switch toward M1 polarization. This study suggests that alcohol-fructose combination contributes to ALD progression.
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.
authors: Ming
authors: M
authors: Song
authors: Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.
authors: Theresa
authors: T
authors: Chen
authors: Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky.
authors: Russell A
authors: RA
authors: Prough
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.|Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.|Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, Kentucky.|Robley Rex Louisville Veterans Affairs Medical Center, Louisville, Kentucky.
authors: Matthew C
authors: MC
authors: Cave
authors: Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky.|Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, Kentucky.|Robley Rex Louisville Veterans Affairs Medical Center, Louisville, Kentucky.
authors: Craig J
authors: CJ
authors: McClain
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects / Q000378:metabolism*; D000437:Alcoholism / Q000378:metabolism*; D000818:Animals; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism*; D005632:Fructose / Q000008:administration & dosage / Q000633:toxicity*; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008297:Male; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D005632:Fructose
keywords: Alcohol; Fructose; Kupffer Cell Activation; M1 Polarization; Nonalcoholic Fatty Liver Disease