title: Impacts of ezetimibe on PCSK9 in rats: study on the expression in different organs and the potential mechanisms.
abstract: BACKGROUND
  Previous studies including our group have indicated the effects of ezetimibe on increased plasma proprotein convertase subtilisin/kexin type 9 (PCSK9) concentration, while the rapid expression in different organs and the potential molecular mechanisms for this impact have not been carefully evaluated.
  
  
  METHODS
  Thirty rats were randomly divided into two groups (n = 15 for each), which were orally administrated with ezetimibe (10 mg/kg/day) or normal saline. Blood samples were obtained at day 3 after orally administration, and the PCSK9 levels were determined by ELISA. We further analyzed the mRNA expression of PCSK9, low-density lipoprotein receptor (LDLR), sterol regulator element-binding protein 2 (SREBP2), and hepatocyte nuclear factor 1 alpha (HNF-1α) by real-time PCR, as well as the protein expression by western blot, in liver, intestine and kidney respectively.
  
  
  RESULTS
  Ezetimibe significantly increased plasma PCSK9 levels compared with control group, while there was no significant difference between the two groups with regard to lipid profile at day 3. Moreover, ezetimibe remarkably increased the expression of PCSK9, LDLR, SREBP2 and HNF-1α in liver. Enhanced expression of PCSK9, LDLR and SREBP2 protein were found in intestine and kidney, while no changes in the expression of HNF-1α were observed in intestine and kidney of rats with ezetimibe treatment.
  
  
  CONCLUSIONS
  The data demonstrated that ezetimibe increased PCSK9 expression through the SREBP2 and HNF-1α pathways in different organs, subsequently resulting in elevated plasma PCSK9 levels prior to the alterations of lipid profile in rats.
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. ruixiaxu@sina.com.
authors.forename: Rui-Xia
authors.initials: RX
authors.lastname: Xu
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. liujunemail1@163.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. lixiaolin@ymail.com.
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Li
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. 517833481@qq.com.
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. 18910162571@163.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. yanjun1123@hotmail.com.
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Jia
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. fw8839@126.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, FuWai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China. lijianjun938@126.com.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Li
mesh_terms: D000818:Animals; D000069438:Ezetimibe / Q000494:pharmacology*; D020869:Gene Expression Profiling; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D009928:Organ Specificity / Q000235:genetics*; D000071449:Proprotein Convertase 9; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D008055:Lipids; D012333:RNA, Messenger; D011973:Receptors, LDL; D051782:Sterol Regulatory Element Binding Protein 2; C510804:PCSK9 protein, rat; D000071449:Proprotein Convertase 9; D012697:Serine Endopeptidases; D000069438:Ezetimibe