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Expression data of the livers in mouse with iso-α-acids intake

ABSTRACT: Scope: Alcoholic liver disease (ALD) is a major cause of chronic liver disease and is induced by alcohol consumption. Acetaldehyde produced by alcohol metabolism enhances the fibrosis of the liver through hepatic stellate cells. Additionally, alcohol administration causes the accumulation of reactive oxygen species (ROS), which induce hepatocyte-injury-mediated lipid peroxidation. The purpose of this study was to investigate the protective effects of iso-α-acids against alcoholic liver injury in hepatocytes in mice. Methods and results: C57BL/6N mice were fed diets containing isomerized hop extract, which mainly consists of iso-α-acids. After 7 days of feeding, acetaldehyde was administered by a single intraperitoneal injection. The acetaldehyde-induced increases in serum AST and ALT levels were suppressed by iso-α-acids intake. Hepatic gene expression analyses showed the upregulation of the glutathione-S-transferase, alcohol dehydrogenase and aldehyde dehydrogenase genes. In vitro, iso-α-acids induced the nuclear translocation of nuclear factor erythroid 2-like 2 (Nfe2l2; Nrf2), a master regulator of antioxidant and detoxifying systems, and upregulated the enzymatic activities of glutathione-S-transferase and aldehyde dehydrogenase. Conclusions: These results suggest that iso-α-acids intake prevents alcoholic liver disease injury by reducing oxidative stress via the Nrf2-mediated pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE140387 | GEO | 2021/02/10

REPOSITORIES: GEO

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Project description:Background and aims: Liver is a major target organ for alcohol-induced disease and the spectrum of pathological states elicited by alcohol in liver comprises steatosis, alcoholic steatohepatitis, progressive fibrosis and cirrhosis, conditions that may progress to hepatocellular carcinoma. Many experimental animal models of alcoholic steatohepatitis exist that vary in duration, mode of alcohol administration and the degree and types of liver injury produced. While most of these models, regardless whether alcohol is administered through liquid diet or intragastrically, produce steatohepatitis and mild fibrosis, it is widely acknowledged that these models fail to fully recapitulate key characteristics of severe forms of alcoholic liver disease, such as alcoholic hepatitis. Recent studies attempted to combine alcohol and fibrosis and achieved promising results in mouse models that achieve some of the key features of alcoholic liver disease accompanied by exacerbated fibrosis and acute renal injury. This study combined a chronic cholestatic liver fibrosis model induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) with a mouse model of intragastric alcohol feeding. Methods: Adult male C57BL6/J mice were treated with 3,5-diethoxycarbonyl-1,4-dihydrocolidine (DDC) containing diet (0.05% w/w) to induce chronic liver fibrosis. Following DDC-induced fibrogenesis, ethyl alcohol (EtOH) (up to 27 g/ kg/day, up to 28 days) was administered continuously to mice via a gastric feeding tube (Tsukamoto-Frenchmodel of alcoholic liver disease). Results: Exposure to DDC or EtOH alone resulted in liver fibrosis or steatosis, respectively. Combined treatment with DDC and EtOH lead to an additive effect on liver injury, as evident by the development of hepatic inflammation, steatosis, and pericellular fibrosis, and by increased serum transaminase levels, compared to mice treated with either agent alone. Liver transcriptomic changes specific to combined treatment group included pathways involved in the cell cycle and DNA damage. Analyses of feces from these mice revealed alcohol-associated changes to the bile acid profile and gut microbiome. Conclusions: Mice treated with DDC and EtOH displayed several key characteristics of human alcoholic hepatitis, including pericellular fibrosis, increased hepatic bacterial load with dysbiosis, reduced capacity of the microbiome to synthesize secondary bile acids.

Project description:This study tested a hypothesis that a population-based approach may identify genetic background-dependent and -independent genes/pathways that modulate alcohol-induced liver injury. A sub-chronic (4 weeks) intra-gastric alcohol infusion (up to 27 g/kg/day) model was used to control for alcohol intake in 15 genetically diverse inbred mouse strains. Urine, serum and liver markers of alcoholic steato-hepatitis were assessed and a wide range of liver damage was observed across the panel. Gene expression profiling was performed on liver tissue collected at the end of the study and statistical models, with strain, degree of liver injury, treatment, and their interaction terms as factors, were used to select transcripts associated with strain-dependent and -independent effects of alcohol on the liver. Translational control of hepatic protein synthesis, related to eukaryotic initiation factors (eiFs) and accessory proteins, was identified as genetic background-independent mode of alcohol-induced liver injury. Interestingly, immune response-related transcription factors signal transducer and activator of transcription 1 (Stat1) and nuclear factor, interleukin 3 regulated (Nfil3/E4bp4) are likely determinants of genetic background-dependent responses to liver injury and alcohol treatment, respectively. Our data demonstrate that a multistrain approach provides critical mechanistic information for understanding genetic factors influencing alcohol toxicity and facilitate identification of novel targets of therapeutic intervention. A high-fat diet or EtOH-containing high-fat diet was administered to 15 strains of mice via gastric tube for 28 days. 3 replicates per strain/diet. Inter-batch normalization was carried out using the ComBat procedure. The supplementary file 'GSE20052_Readme.txt' contains a description of the replicates used for normalization. The 'GSE20052_US14702406_25148681*' files linked to the GSE20052 record are the raw data files for the replicates.

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Expression data of the livers in mouse with iso-α-acids intake

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