title: Polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating proprotein convertase subtilisin/kexin type 9 (PCSK9).
abstract: BACKGROUND
  Abnormalities in lipid and glucose metabolism are constantly observed in type 2 diabetes. However, these abnormalities can be ameliorated by polydatin. Considering the important role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in metabolic diseases, we explore the possible mechanism of polydatin on lipid and glucose metabolism through its effects on PCSK9.
  
  
  METHODS
  An insulin-resistant HepG2 cell model induced by palmitic acid (PA) and a db/db mice model were used to clarify the role of polydatin on lipid and glucose metabolism.
  
  
  RESULTS
  In insulin-resistant HepG2 cells, polydatin upregulated the protein levels of LDLR and GCK but repressed PCSK9 protein expression, besides, polydatin also inhibited the combination between PCSK9 and LDLR. Knockdown and overexpression experiments indicated that polydatin regulated LDLR and GCK expressions through PCSK9. In the db/db mice model, we found that polydatin markedly enhanced GCK and LDLR protein levels, and inhibited PCSK9 expression in the liver. Molecular docking assay was further performed to analyze the possible binding mode between polydatin and the PCSK9 crystal structure (PDB code: 2p4e), which indicated that steady hydrogen bonds formed between polydatin and PCSK9.
  
  
  CONCLUSIONS
  Our study indicates that polydatin ameliorates lipid and glucose metabolism in type 2 diabetes mellitus by downregulating PCSK9.
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 WaiHuan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China. wangyuyaoxue@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 WaiHuan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China. yejt@mail.sysu.edu.cn.|National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou, 510006, China. yejt@mail.sysu.edu.cn.
authors.forename: Jiantao
authors.initials: J
authors.lastname: Ye
authors.affiliation: Laboratory Animal Center, Sun Yat-sen University, Guangzhou, 510080, China. celiagz@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 WaiHuan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China. chencheng4610@163.com.
authors.forename: Cheng
authors.initials: C
authors.lastname: Chen
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 WaiHuan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China. 919808259@qq.com.
authors.forename: Junying
authors.initials: J
authors.lastname: Huang
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 WaiHuan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China. liupq@mail.sysu.edu.cn.|National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou, 510006, China. liupq@mail.sysu.edu.cn.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, 132 WaiHuan East Road, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China. huangheq@mail.sysu.edu.cn.|Laboratory Animal Center, Sun Yat-sen University, Guangzhou, 510080, China. huangheq@mail.sysu.edu.cn.|National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangzhou, 510006, China. huangheq@mail.sysu.edu.cn.
authors.forename: Heqing
authors.initials: H
authors.lastname: Huang
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D004365:Drugs, Chinese Herbal / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D000081410:Germinal Center Kinases; D005960:Glucosides / Q000378:metabolism / Q000494:pharmacology*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D006860:Hydrogen Bonding; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D062105:Molecular Docking Simulation; D019308:Palmitic Acid / Q000494:pharmacology; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D004365:Drugs, Chinese Herbal; D000081410:Germinal Center Kinases; D005960:Glucosides; D007004:Hypoglycemic Agents; C573412:LDLR protein, human; D008055:Lipids; D011973:Receptors, LDL; D013267:Stilbenes; D019308:Palmitic Acid; D017346:Protein Serine-Threonine Kinases; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; C058229:polydatin
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