Adipocyte-derived Lysophosphatidylcholine Activates Adipocyte and Adipose Tissue Macrophage Nod-Like Receptor Protein 3 Inflammasomes Mediating Homocysteine-Induced Insulin Resistance

  • EBioMedicine. 2018 May;31:202-216. doi: 10.1016/j.ebiom.2018.04.022.
Song-Yang Zhang  1 ,  Yong-Qiang Dong  1 ,  Pengcheng Wang  1 ,  Xingzhong Zhang  1 ,  Yu Yan  1 ,  Lulu Sun  1 ,  Bo Liu  1 ,  Dafang Zhang  2 ,  Heng Zhang  3 ,  Huiying Liu  1 ,  Wei Kong  1 ,  Gang Hu  4 ,  Yatrik M Shah  5 ,  Frank J Gonzalez  6 ,  Xian Wang  7 ,  Changtao Jiang  8
Affiliations
  • 1. 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.
  • 2. Department of Hepatobiliary Surgery, Peking University People's Hospital, Peking University, Beijing 100044, People's Republic of China.
  • 3. Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, People's Republic of China.
  • 4. 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.
  • 5. Department of Molecular & Integrative Physiology, Division of Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 6. Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • 7. 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. Electronic address: [email protected].
  • 8. 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. Electronic address: [email protected].
PMID: 29735414 DOI: 10.1016/j.ebiom.2018.04.022
Abstract

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
Adipocyte; Adipose tissue macrophage; Homocysteine; Insulin resistance; NLRP3 inflammasome.
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