한빛사논문
- 조회2,889
Seung-Jin Kim1, Dechun Feng1, Adrien Guillot1, Shen Dai,2 Fengming Liu,2 Seonghwan Hwang,1 Richard Parker1, 3, Wonhyo Seo1, Yong He1, Grzegorz Godlewski 4, Won-IlJeong1, 5, Yuhong Lin,6 Xuebin Qin2, George Kunos,4 and Bin Gao1*
1 Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Bethesda, MD 20892, USA; 2 Department of Neuroscience, School of Medicine,Temple University, Philadelphia, PA, USA; 3 NIHR Centre for Liver Research, University of Birmingham, UK; 4 Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health,Bethesda, MD 20892;USA; 5 Laboratory of Liver Research, Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon34141, Republic of Korea 6 Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892; USA
*Corresponding author : Bin Gao, M.D., Ph.D., Laboratory of Liver Diseases, NIAAA/NIH, 5625 Fishers Lane, Bethesda, MD 20892
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 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.
논문정보
- Research article
- 2019년 01월 (BRIC 등록일 2019-02-08)
- 국내+국외 연구진
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