title: Cluster of Differentiation 36 Deficiency Aggravates Macrophage Infiltration and Hepatic Inflammation by Upregulating Monocyte Chemotactic Protein-1 Expression of Hepatocytes Through Histone Deacetylase 2-Dependent Pathway.
abstract: Cluster of differentiation 36 (CD36) is involved in the development of nonalcoholic steatohepatitis (NASH). Excess CD36 facilitates liver cells taking fatty acid and activates inflammatory signals to promote hepatic steatosis and inflammation. However, CD36 deficiency paradoxically promotes nonalcoholic fatty liver disease by unknown mechanisms. We explored the probable molecular mechanism of hepatic inflammation induced by CD36 deficiency.
  
  
  
  CD36 deletion in mice (CD36-/-mice) specifically increased monocyte chemotactic protein-1 (MCP-1) in hepatocytes, promoted macrophage migration to the liver, and aggravated hepatic inflammatory response and fibrosis. The nuclear expression of histone deacetylase 2 (HDAC2), which highly expresses in wild-type hepatocytes and has an inhibitory effect on acetyl histone 3 (H3), was reduced in CD36-deficient hepatocytes. Consequently, the level of acetyl H3 binding to MCP-1 promoters was increased in CD36-deficient hepatocytes, causing hepatic-specific MCP-1 transcriptional activation. Reduction of nuclear HDAC2 in both CD36-/-mice liver and cultured hepatocytes was due to reduction of intracellular reactive oxygen species (ROS) level, while supplement of low-concentration hydrogen peroxide (H2O2) overcame the suppression of HDAC2 caused by CD36 deficiency, decreasing MCP-1 gene transcription and microphage migration.
  
  
  
  Our results provide first evidence that decreased ROS production by CD36 deletion was also harmful for livers. The fine balance of CD36 plays an important role in maintaining balances of hepatic ROS and nuclear HDAC2, which could be a potential new therapeutic strategy for the prevention of NASH development.
  
  
  
  CD36 deficiency promoted the development of NASH by facilitating the transcription of MCP-1 in hepatocytes due to the reduction of ROS and nuclear HDAC2. Antioxid. Redox Signal. 00, 000-000.
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .
authors.forename: Chang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: 2 John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London , London, United Kingdom .
authors.forename: Zac
authors.initials: Z
authors.lastname: Varghese
authors.affiliation: 2 John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London , London, United Kingdom .
authors.forename: John F
authors.initials: JF
authors.lastname: Moorhead
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .
authors.forename: Yaxi
authors.initials: Y
authors.lastname: Chen
authors.affiliation: 1 Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University , Chongqing, China .|2 John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London , London, United Kingdom .|3 The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (CCID), Zhejiang University , Hangzhou, China .|4 Centre for Nephrology and Urology, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China .
authors.forename: Xiong Z
authors.initials: XZ
authors.lastname: Ruan
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000172:deficiency* / Q000235:genetics; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000074084:THP-1 Cells; D015854:Up-Regulation
chemical_list: D018955:CD36 Antigens; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D006657:Histones; D017382:Reactive Oxygen Species; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2
keywords: CD36; MCP-1; NASH; ROS