Short- or long-term high-fat diet feeding plus acute ethanol binge synergistically induce acute liver injury in mice: An important role for CXCL1

被引：163

作者：

Chang, Binxia ^{[1
,3
]}

Xu, Ming-Jiang ^{[1
]}

Zhou, Zhou ^{[1
]}

Cai, Yan ^{[1
]}

Li, Man ^{[1
]}

Wang, Wei ^{[1
]}

Feng, Dechun ^{[1
]}

Bertola, Adeline ^{[1
]}

Wang, Hua ^{[1
]}

Kunos, George ^{[2
]}

Gao, Bin ^{[1
]}

机构：

[1] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA

[2] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA

[3] Beijing 302 Hosp, Inst Alcohol Liver Dis, Diag & Treatment Ctr Noninfect Liver Dis, Beijing, Peoples R China

来源：

HEPATOLOGY | 2015年 / 62卷 / 04期

基金：

美国国家卫生研究院;

关键词：

INDUCED NEUTROPHIL CHEMOATTRACTANT; INDUCED INSULIN-RESISTANCE; GENETICALLY-OBESE MICE; BODY-MASS INDEX; ACETAMINOPHEN HEPATOTOXICITY; ALCOHOL-CONSUMPTION; ADIPOSE-TISSUE; RISK-FACTORS; RAT-LIVER; DISEASE;

D O I：

10.1002/hep.27921

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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 B. 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. (Hepatology 2015;62:1070-1085)

引用

页码：1070 / 1085

页数：16

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[1] Effect of moderate alcohol consumption on liver enzymes increases with increasing body mass index [J].