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Chronic Alcohol Consumption Causes Liver Injury in High‐Fructose‐Fed Male Mice Through Enhanced Hepatic Inflammatory Response
Author(s) -
Song Ming,
Chen Theresa,
Prough Russell A.,
Cave Matthew C.,
McClain Craig J.
Publication year - 2016
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12994
Subject(s) - steatosis , fructose , medicine , endocrinology , fatty liver , liver injury , high fructose corn syrup , metabolic syndrome , alcoholic liver disease , ingestion , alanine transaminase , chemistry , biology , obesity , biochemistry , cirrhosis , disease
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 C57 BL /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 KC s and activation marker gene expression, including Emr1, CD 68, and CD 163. 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 TLR 4 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.