The liver is an organ with strong innate immunity, which plays an important role in host defense against microbial infection and tumor transformation. Emerging evidence suggests that innate immunity as well as a variety of cytokines produced by innate immune cells also contribute to the pathogenesis of acute and chronic liver diseases. Our laboratory has been actively studying the role of innate immunity and its associated cytokines in liver injury and repair. During the fiscal year, we have demonstrated that adipose tissues-associated macrophages play an important role in the pathogenesis of liver injury and inflammation. We have demonstrated that adipocyte death preferentially induces liver injury and inflammation through the activation of chemokine (C-C Motif) receptor 2-positive macrophages and lipolysis. Abstract: Adipocyte death occurs under various physiopathological conditions, including obesity and alcohol drinking, and can trigger organ damage particularly in the liver, but the underlying mechanisms remain obscure. To explore these mechanisms, we developed a mouse model of inducible adipocyte death by overexpressing the human CD59 (hCD59) on adipocytes (adipocyte-specific hCD59 transgenic mice). Injection of these mice with intermedilysin (ILY), which rapidly lyses hCD59 expressing cells exclusively by binding to the hCD59 but not mouse CD59, resulted in the acute selective death of adipocytes, adipose macrophage infiltration, and elevation of serum free fatty acid (FFA) levels. ILY injection also resulted in the secondary damage to multiple organs with the strongest injury observed in the liver, with inflammation and hepatic macrophage activation. Mechanistically, acute adipocyte death elevated epinephrine and norepinephrine levels and activated lipolysis pathways in adipose tissue in a chemokine (C-C motif) receptor 2-positive (CCR2+ ) macrophage-dependent manner, which was followed by FFA release and lipotoxicity in the liver. Additionally, acute adipocyte death caused hepatic CCR2+ macrophage activation and infiltration, further exacerbating liver injury. Conclusion: Adipocyte death predominantly induces liver injury and inflammation, which is probably due to the superior sensitivity of hepatocytes to lipotoxicity and the abundance of macrophages in the liver.

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Budget End
Support Year
18
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
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Chen, Hanqing; Shen, Feng; Sherban, Alex et al. (2018) DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease. Hepatology 68:496-514
Guillot, Adrien; Gasmi, Imène; Brouillet, Arthur et al. (2018) Interleukins-17 and 27 promote liver regeneration by sequentially inducing progenitor cell expansion and differentiation. Hepatol Commun 2:329-343
Li, Hongjie; Feng, Dechun; Cai, Yan et al. (2018) Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin-2 and neutrophil extracellular traps. Hepatology 68:1604-1620
Jiang, Yiming; Feng, Dechun; Ma, Xiaochao et al. (2018) Pregnane X Receptor Regulates Liver Size and Liver Cell Fate via Yes-associated Protein Activation. Hepatology :
Alves-Paiva, Raquel M; Kajigaya, Sachiko; Feng, Xingmin et al. (2018) Telomerase enzyme deficiency promotes metabolic dysfunction in murine hepatocytes upon dietary stress. Liver Int 38:144-154
Ouyang, Xinshou; Han, Sheng-Na; Zhang, Ji-Yuan et al. (2018) Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1? Transactivation in Steatohepatitis. Cell Metab 27:339-350.e3
Gao, Bin; Xiang, Xiaogang (2018) Interleukin-22 from bench to bedside: a promising drug for epithelial repair. Cell Mol Immunol :
Shi, Jijing; Zhao, Juanjuan; Zhang, Xin et al. (2017) Activated hepatic stellate cells impair NK cell anti-fibrosis capacity through a TGF-?-dependent emperipolesis in HBV cirrhotic patients. Sci Rep 7:44544
He, Yong; Feng, Dechun; Li, Man et al. (2017) Hepatic mitochondrial DNA/Toll-like receptor 9/MicroRNA-223 forms a negative feedback loop to limit neutrophil overactivation and acetaminophen hepatotoxicity in mice. Hepatology 66:220-234
Wang, Meng; Frasch, S Courtney; Li, Guiying et al. (2017) Role of gp91phox in hepatic macrophage programming and alcoholic liver disease. Hepatol Commun 1:765-779

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