Adipocyte-derived Lysophosphatidylcholine Activates Adipocyte and Adipose Tissue Macrophage Nod-Like Receptor Protein 3 Inflammasomes Mediating Homocysteine-Induced Insulin Resistance
Song-Yang Zhang,
Yong-Qiang Dong,
Pengcheng Wang,
Xingzhong Zhang,
Yu Yan,
Lulu Sun,
Bo Liu,
Dafang Zhang,
Heng Zhang,
Huiying Liu,
Wei Kong,
Gang Hu,
Yatrik M. Shah,
Frank J. Gonzalez,
Xian Wang,
Changtao Jiang
Affiliations
Song-Yang Zhang
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China
Yong-Qiang Dong
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China
Pengcheng Wang
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China
Xingzhong Zhang
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China
Yu Yan
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China
Lulu Sun
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China
Bo Liu
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China
Dafang Zhang
Department of Hepatobiliary Surgery, Peking University People's Hospital, Peking University, Beijing 100044, People's Republic of China
Heng Zhang
Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China
Huiying Liu
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China
Wei Kong
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China
Gang Hu
Department of Pharmacology, School of Basic Medical Sciences, Nanjing Medical University, Jiangsu Key Laboratory of Neurodegeneration, Nanjing 210029, Jiangsu, People's Republic of China; Department of Pharmacology, School of Basic Medical Sciences, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, People's Republic of China
Yatrik M. Shah
Department of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA
Frank J. Gonzalez
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
Xian Wang
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China; Corresponding authors at: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, People's Republic of China.
Changtao Jiang
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, People's Republic of China; Corresponding authors at: Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Beijing 100191, People's Republic of China.
The adipose Nod-like receptor protein 3 (NLRP3) inflammasome senses danger-associated molecular patterns (DAMPs) and initiates insulin resistance, but the mechanisms of adipose inflammasome activation remains elusive. In this study, Homocysteine (Hcy) is revealed to be a DAMP that activates adipocyte NLRP3 inflammasomes, participating in insulin resistance. Hcy-induced activation of NLRP3 inflammasomes were observed in both adipocytes and adipose tissue macrophages (ATMs) and mediated insulin resistance. Lysophosphatidylcholine (lyso-PC) acted as a second signal activator, mediating Hcy-induced adipocyte NLRP3 inflammasome activation. Hcy elevated adipocyte lyso-PC generation in a hypoxia-inducible factor 1 (HIF1)-phospholipase A2 group 16 (PLA2G16) axis-dependent manner. Lyso-PC derived from the Hcy-induced adipocyte also activated ATM NLRP3 inflammasomes in a paracrine manner. This study demonstrated that Hcy activates adipose NLRP3 inflammasomes in an adipocyte lyso-PC-dependent manner and highlights the importance of the adipocyte NLRP3 inflammasome in insulin resistance. Keywords: Insulin resistance, NLRP3 inflammasome, Homocysteine, Adipocyte, Adipose tissue macrophage
