Seung-Jin Kim1, Dechun Feng1, Adrien Guillot1, Shen Dai2, Fengming Liu2, Seonghwan Hwang1, Richard Parker1,3, Wonhyo Seo1, Yong He1, Grzegorz Godlewski4, Won-Il Jeong1,5, Yuhong Lin6, Xuebin Qin2, George Kunos4, Bin Gao1. 1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD. 2. Department of Neuroscience, School of Medicine, Temple University, Philadelphia, PA. 3. NIHR Centre for Liver Research, University of Birmingham, Birmingham, United Kingdom. 4. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD. 5. Laboratory of Liver Research, Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. 6. Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
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. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.
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. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.
Authors: Saverio Cinti; Grant Mitchell; Giorgio Barbatelli; Incoronata Murano; Enzo Ceresi; Emanuela Faloia; Shupei Wang; Melanie Fortier; Andrew S Greenberg; Martin S Obin Journal: J Lipid Res Date: 2005-09-08 Impact factor: 5.922
Authors: Utpal B Pajvani; Maria E Trujillo; Terry P Combs; Puneeth Iyengar; Linda Jelicks; Kevin A Roth; Richard N Kitsis; Philipp E Scherer Journal: Nat Med Date: 2005-06-19 Impact factor: 53.440
Authors: Stuart P Weisberg; Deborah Hunter; Reid Huber; Jacob Lemieux; Sarah Slaymaker; Kris Vaddi; Israel Charo; Rudolph L Leibel; Anthony W Ferrante Journal: J Clin Invest Date: 2005-12-08 Impact factor: 14.808
Authors: Kimberly M Hargrave; ChangLong Li; Brett J Meyer; Stephen D Kachman; Diane L Hartzell; Mary Anne Della-Fera; Jess L Miner; Clifton A Baile Journal: Obes Res Date: 2002-12
Authors: Elizabeth C Stahl; Evan R Delgado; Frances Alencastro; Samuel T LoPresti; Patrick D Wilkinson; Nairita Roy; Martin J Haschak; Clint D Skillen; Satdarshan P Monga; Andrew W Duncan; Bryan N Brown Journal: Am J Pathol Date: 2019-12-13 Impact factor: 4.307
Authors: Brenna R Kaelin; Collin M McKenzie; Karl W Hempel; Anna L Lang; Gavin E Arteel; Juliane I Beier Journal: Toxicol Appl Pharmacol Date: 2020-05-20 Impact factor: 4.219