Song Ming, Chen Theresa, Prough Russell A, Cave Matthew C, McClain Craig J
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.
Alcohol Clin Exp Res. 2016 Mar;40(3):518-28. doi: 10.1111/acer.12994. Epub 2016 Feb 9.
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).
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.
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.
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.
肥胖和代谢综合征在大约三分之一的酒精性肝病（ALD）患者中出现。在美国和全球范围内，果糖消费量的增加与肥胖和代谢综合征患病率的上升同步。在本研究中，我们调查了高果糖饮食是否会增强慢性酒精诱导的肝损伤，并探索了潜在机制。
将六周龄雄性C57BL/6J小鼠分为4组：对照组、高果糖组、慢性乙醇（EtOH）组和高果糖加慢性酒精组。给小鼠喂食对照饮食或高果糖饮食（60%，w/w）18周。从第9周开始至第18周，给慢性酒精喂养的小鼠随意饮用20%（v/v）乙醇（Meadows-Cook模型）作为唯一可用液体。评估肝损伤、脂肪变性、肝脏炎症基因表达和铜状态。
单独的高果糖饮食和慢性酒精消费均会诱导肝脏脂肪堆积并损害铜状态。然而，高果糖饮食加慢性酒精的组合协同诱导肝损伤，血浆丙氨酸转氨酶和天冬氨酸转氨酶大幅升高证明了这一点，但该组合并未加剧肝脏脂肪堆积，也未使铜状态恶化。此外，喂食乙醇的小鼠以明显的微泡性脂肪变性为特征。高果糖饮食和慢性酒精摄入共同导致库普弗细胞（KC）M1表型基因表达（如肿瘤坏死因子-α和单核细胞趋化蛋白-1）以及Toll样受体4（TLR4）信号基因表达显著上调，这也与KC上调和激活标记基因表达（包括Emr1、CD68和CD163）上调相关。
我们的数据表明，高果糖饮食可能会增强慢性酒精消费诱导的肝损伤。潜在机制可能是高果糖饮食和酒精对TLR4信号通路激活的协同作用，进而导致KC激活和表型向M1极化转变。本研究表明，酒精-果糖组合会促进ALD进展。
