title: Retinol-Binding Protein-Dependent Cholesterol Uptake Regulates Macrophage Foam Cell Formation and Promotes Atherosclerosis.
abstract: BACKGROUND
  Retinol-binding protein 4 (RBP4) is an adipokine that plays decisive roles in glucose metabolism and insulin sensitivity. Elevated circulating RBP4 levels were reported to be associated with increased risk for cardiovascular disease, but the precise role of RBP4 in atherosclerotic diseases and its mechanisms of action remain elusive.
  
  
  METHODS
  Serum RBP4 levels of 1683 participants from South China were evaluated and the occurrence of major adverse cardiovascular events was followed up for 5 years. Apolipoprotein E-deficient mice infected with RBP4-overexpressing/silencing adenovirus, J774A.1 macrophages, and primary peritoneal macrophages from RBP4 transgenic mice were used for investigating the function of RBP4 in foam cell formation.
  
  
  RESULTS
  Prospective cohort studies revealed that baseline serum RBP4 level was an independent predictor for incidence of adverse cardiovascular events after adjustment for traditional risk factors. Increased RBP4 expression was observed in atherosclerotic lesions of aortic specimens from both humans and apolipoprotein E-deficient mice, and RBP4 was localized to areas rich in macrophage foam cells. RBP4 inhibition attenuated whereas overexpression accelerated atherosclerosis progression in apolipoprotein E-deficient mice. Both treatment with exogenous recombinant RBP4 and overexpression of RBP4 gene promoted macrophage-derived foam cell formation through the activation of scavenger-receptor CD36-mediated cholesterol uptake, and RBP4 transcriptionally upregulated CD36 expression in a manner dependent on jun N-terminal kinase and signal transducer and activator of transcription 1. The tyrosine kinase c-Src was identified as the upstream regulator of jun N-terminal kinase-signal transducer and activator of transcription 1-mediated CD36-dependent cholesterol uptake, and RBP4 challenge was found to alter the membrane distribution of c-Src and cause c-Src to partition into lipid-raft membrane subdomains, where the kinase was activated. Lastly, Toll-like receptor 4, but not retinol or stimulated by retinoic acid 6, mediated the inductive effects of RBP4 in macrophages.
  
  
  CONCLUSIONS
  Inclusion of RBP4 levels in traditional models enhances the predictive ability for the incidence of atherosclerotic events. RBP4 promotes atherogenesis by inducing macrophage-derived foam cell formation.
authors.affiliation: From Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, People's Republic of China (Y.L.); and Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China (J.-S.O.).
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, People's Republic of China (Y.L.); and Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China (J.-S.O.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: From Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, People's Republic of China (Y.L.); and Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China (J.-S.O.).
authors.forename: Hongen
authors.initials: H
authors.lastname: Chen
authors.affiliation: From Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, People's Republic of China (Y.L.); and Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China (J.-S.O.).
authors.forename: Duan
authors.initials: D
authors.lastname: Wang
authors.affiliation: From Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, People's Republic of China (Y.L.); and Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China (J.-S.O.).
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: From Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, People's Republic of China (Y.L.); and Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China (J.-S.O.).
authors.forename: Jing-Song
authors.initials: JS
authors.lastname: Ou
authors.affiliation: From Guangdong Provincial Key Laboratory of Food, Nutrition and Health, Guangzhou, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus), Guangzhou, Guangdong Province, People's Republic of China (Y.L., Y.Z., H.C., D.W., M.W., M.X.); State Key Laboratory of Pharmaceutical Biotechnology, Department of Medicine, University of Hong Kong, People's Republic of China (Y.L.); and Division of Cardiac Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China (J.-S.O.). xiamin@mail.sysu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Xia
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000209:etiology* / Q000473:pathology; D002352:Carrier Proteins; D015331:Cohort Studies; D005487:Foam Cells / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010196:Pancreatic Elastase; D011446:Prospective Studies; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D002352:Carrier Proteins; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; D010196:Pancreatic Elastase; C017130:cholesterol-binding protein
keywords: CD36; RBP4; atherosclerosis; cholesterol uptake