Browsing by Author "Xu, Ming-Jiang"

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    Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance
    (Ingenta, 2017-07-07) Gao, Bin; Xu, Ming-Jiang; Bertola, Adeline; Wang, Hua; Zhou, Zhou; Liangpunsakul, Suthat; Medicine, School of Medicine
    Alcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and to test for therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed.
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    Ethanol and its Nonoxidative Metabolites Promote Acute Liver Injury by Inducing ER Stress, Adipocyte Death, and Lipolysis
    (Elsevier, 2023) Park, Seol Hee; Seo, Wonhyo; Xu, Ming-Jiang; Mackowiak, Bryan; Lin, Yuhong; He, Yong; Fu, Yaojie; Hwang, Seonghwan; Kim, Seung-Jin; Guan, Yukun; Feng, Dechun; Yu, Liqing; Lehner, Richard; Liangpunsakul, Suthat; Gao, Bin; Medicine, School of Medicine
    Background & aims: Binge drinking in patients with metabolic syndrome accelerates the development of alcohol-associated liver disease. However, the underlying mechanisms remain elusive. We investigated if oxidative and nonoxidative alcohol metabolism pathways, diet-induced obesity, and adipose tissues influenced the development of acute liver injury in a single ethanol binge model. Methods: A single ethanol binge was administered to chow-fed or high-fat diet (HFD)-fed wild-type and genetically modified mice. Results: Oral administration of a single dose of ethanol induced acute liver injury and hepatic endoplasmic reticulum (ER) stress in chow- or HFD-fed mice. Disruption of the Adh1 gene increased blood ethanol concentration and exacerbated acute ethanol-induced ER stress and liver injury in both chow-fed and HFD-fed mice, while disruption of the Aldh2 gene did not affect such hepatic injury despite high blood acetaldehyde levels. Mechanistic studies showed that alcohol, not acetaldehyde, promoted hepatic ER stress, fatty acid synthesis, and increased adipocyte death and lipolysis, contributing to acute liver injury. Increased serum fatty acid ethyl esters (FAEEs), which are formed by an enzyme-mediated esterification of ethanol with fatty acids, were detected in mice after ethanol gavage, with higher levels in Adh1 knockout mice than in wild-type mice. Deletion of the Ces1d gene in mice markedly reduced the acute ethanol-induced increase of blood FAEE levels with a slight but significant reduction of serum aminotransferase levels. Conclusions: Ethanol and its nonoxidative metabolites, FAEEs, not acetaldehyde, promoted acute alcohol-induced liver injury by inducing ER stress, adipocyte death, and lipolysis.
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    Interleukin 8/KC enhances G-CSF induced hematopoietic stem/progenitor cell mobilization in Fancg deficient mice
    (AME Publishing Company, 2014) Li, Yan; Xing, Wen; He, Yong-Zheng; Chen, Shi; Rhodes, Steven D.; Yuan, Jin; Zhou, Yuan; Shi, Jun; Bai, Jie; Zhang, Feng-Kui; Yuan, Wei-Ping; Cheng, Tao; Xu, Ming-Jiang; Yang, Feng-Chun; Department of Pediatrics, IU School of Medicine
    BACKGROUND: Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by a progressive bone marrow aplasia, chromosomal instability, and acquisition of malignancies. Successful hematopoietic cell transplantation (HCT) for FA patients is challenging due to hypersensitivity to DNA alkylating agents and irradiation of FA patients. Early mobilization of autologous stem cells from the bone marrow has been thought to be ideal prior to the onset of bone marrow failure, which often occurs during childhood. However, the markedly decreased response of FA hematopoietic stem cells to granulocyte colony-stimulating factor (G-CSF) is circumventive of this autologous HCT approach. To-date, the mechanism for defective stem cell mobilization in G-CSF treated FA patients remains unclear. METHODS: Fancg heterozygous (Fancg (+/-)) mice utilized in these studies. Student's t-test and one-way ANOVA were used to evaluate statistical differences between WT and Fancg (-/-) cells. Statistical significance was defined as P values less than 0.05. RESULTS: Fancg deficient (Fancg (-/-)) mesenchymal stem/progenitor cells (MSPCs) produce significant lower levels of KC, an interleukin-8 (IL-8) related chemoattractant protein in rodents, as compared to wild type cells. Combinatorial administration of KC and G-CSF significantly increased the mobilization of hematopoietic stem/progenitor cells (HSPCs) in Fancg (-/-) mice. CONCLUSIONS: In summary, our results suggest that KC/IL-8 could be proved useful in the synergistic mobilization of FA HSPCs in combination with G-CSF.
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    Mitochondrial DNA-enriched microparticles promote acute-on-chronic alcoholic neutrophilia and hepatotoxicity
    (American Society for Clinical Investigation, 2017-07-20) Cai, Yan; Xu, Ming-Jiang; Koritzinsky, Erik H.; Zhou, Zhou; Wang, Wei; Cao, Haixia; Yuen, Peter S.T.; Ross, Ruth A.; Star, Robert A.; Liangpunsaku, Suthat; Gao, Bin; Medicine, School of Medicine
    Over the last several years, one of the major advances in the field of alcoholic liver disease research was the discovery that binge alcohol consumption induced neutrophilia and hepatic neutrophil infiltration in chronically ethanol-fed mice and human subjects with excessive alcohol use (EAU); however, the underlying mechanisms remain obscure. Here, we demonstrated that chronic EAU patients with a history of recent excessive drinking (EAU + RD) had higher serum levels of mitochondrial DNA (mtDNA)-enriched microparticles (MPs) than EAU without recent drinking (EAU - RD) and healthy controls, which correlated positively with circulating neutrophils. Similarly, mice with chronic-plus-binge (E10d + 1B) ethanol feeding also had markedly elevated serum levels of mtDNA-enriched MPs, with activation of hepatic ER stress and inflammatory responses. Inhibition of ER stress by gene KO or inhibitors attenuated ethanol-induced elevation of mtDNA-enriched MPs, neutrophilia, and liver injury. The data from the study of hepatocyte-specific deletion of the protein kinase RNA-like ER kinase (Perk) gene in mice and of cultured hepatocytes demonstrated that hepatocytes were the main source of mtDNA-enriched MPs after ethanol feeding. Finally, administration of mtDNA-enriched MPs isolated from E10d+1B-fed mice caused neutrophilia in mice. In conclusion, E10d + 1B ethanol consumption activates hepatic ER stress-dependent mtDNA-enriched MP release, leading to neutrophilia and liver injury.