title: Fibroblast growth factor 21 prevents atherosclerosis by suppression of hepatic sterol regulatory element-binding protein-2 and induction of adiponectin in mice.
abstract: BACKGROUND
  Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. It acts as a key downstream target of both peroxisome proliferator-activated receptor α and γ, the agonists of which have been used for lipid lowering and insulin sensitization, respectively. However, the role of FGF21 in the cardiovascular system remains elusive.
  
  
  RESULTS
  The roles of FGF21 in atherosclerosis were investigated by evaluating the impact of FGF21 deficiency and replenishment with recombinant FGF21 in apolipoprotein E(-/-) mice. FGF21 deficiency causes a marked exacerbation of atherosclerotic plaque formation and premature death in apolipoprotein E(-/-) mice, which is accompanied by hypoadiponectinemia and severe hypercholesterolemia. Replenishment of FGF21 protects against atherosclerosis in apolipoprotein E(-/-)mice via 2 independent mechanisms, inducing the adipocyte production of adiponectin, which in turn acts on the blood vessels to inhibit neointima formation and macrophage inflammation, and suppressing the hepatic expression of the transcription factor sterol regulatory element-binding protein-2, thereby leading to reduced cholesterol synthesis and attenuation of hypercholesterolemia. Chronic treatment with adiponectin partially reverses atherosclerosis without obvious effects on hypercholesterolemia in FGF21-deficient apolipoprotein E(-/-) mice. By contrast, the cholesterol-lowering effects of FGF21 are abrogated by hepatic expression of sterol regulatory element-binding protein-2.
  
  
  CONCLUSIONS
  FGF21 protects against atherosclerosis via fine tuning the multiorgan crosstalk among liver, adipose tissue, and blood vessels.
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Zhuofeng
authors: Z
authors: Lin
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Xuebo
authors: X
authors: Pan
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Fan
authors: F
authors: Wu
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Dewei
authors: D
authors: Ye
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Yi
authors: Y
authors: Zhang
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Yu
authors: Y
authors: Wang
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Leigang
authors: L
authors: Jin
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Qizhou
authors: Q
authors: Lian
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Yu
authors: Y
authors: Huang
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Hong
authors: H
authors: Ding
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Chris
authors: C
authors: Triggle
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.).
authors: Kai
authors: K
authors: Wang
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.). amxu@hku.hk xiaokunli@wzmc.edu.cn.
authors: Xiaokun
authors: X
authors: Li
authors: From School of Pharmaceutical Science, Wenzhou Medical University, China (Z.L., X.P., Y.Z., L.J., X.L., A.X.); Engineering Research Center of Bioreactor and Pharmaceutical Development, Ministry of Education, Jilin Agricultural University, Changchun, China (F.W., X.L.); State Key Laboratory of Pharmaceutical Biotechnology (D.Y., Y.W., Q.L., A.X.), Departments of Medicine (D.Y., Q.L., A.X.) and Pharmacology and Pharmacy (D.Y., Y.W., A.X.), University of Hong Kong, China; School of Biomedical Sciences, Chinese University of Hong Kong, China (Y.H.); Department of Pharmacology, Weill Cornell Medical College in Qatar, Doha (H.D., C.T.); and Department of Neurology, 1st Affiliated Hospital of Anhui Medical University, Hefei, China (K.W.). amxu@hku.hk xiaokunli@wzmc.edu.cn.
authors: Aimin
authors: A
authors: Xu
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D052242:Adiponectin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002784:Cholesterol / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005346:Fibroblast Growth Factors / Q000172:deficiency / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000187:drug effects; D006938:Hyperlipoproteinemia Type II / Q000150:complications / Q000235:genetics / Q000378:metabolism; D000090265:Klotho Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000187:drug effects / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D051782:Sterol Regulatory Element Binding Protein 2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D001057:Apolipoproteins E; C418622:Klb protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D002784:Cholesterol; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D000090265:Klotho Proteins
keywords: adipokines; atherosclerosis; fibroblast growth factor 21; hormones