title: Enhanced pro-protein convertase subtilisin/kexin type 9 expression by C-reactive protein through p38MAPK-HNF1α pathway in HepG2 cells.
abstract: Plasma C-reactive protein (CRP) concentration is associated positively with cardiovascular risk, including dyslipidemia. We suggested a regulating role of CRP on pro-protein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein (LDL) metabolism, and demonstrated the PCSK9 as a pathway linking CRP and LDL regulation. Firstly, experiments were carried out in the presence of human CRP on the protein and mRNA expression of PCSK9 and LDL receptor (LDLR) in human hepatoma cell line HepG2 cells. Treatment with CRP (10 μg/ml) enhanced significantly the mRNA and protein expression of PCSK9 and suppressed the expression of LDLR. Of note, a late return of LDLR mRNA levels occurred at 12 hrs, while the LDLR protein continued to decrease at 24 hrs, suggesting that the late decrease in LDLR protein levels was unlikely to be accounted for the decrease in LDL mRNA. Secondly, the role of PCSK9 in CRP-induced LDLR decrease and the underlying pathways were investigated. As a result, the inhibition of PCSK9 expression by small interfering RNA (siRNA) returned partly the level of LDLR protein and LDL uptake during CRP treatment; CRP-induced PCSK9 increase was inhibited by the p38MAPK inhibitor, SB203580, resulting in a significant rescue of LDLR protein expression and LDL uptake; the pathway was involved in hepatocyte nuclear factor 1α (HNF1α) but not sterol responsive element-binding proteins (SREBPs) preceded by the phosphorylation of p38MAPK. These findings indicated that CRP increased PCSK9 expression by activating p38MAPK-HNF1α pathway, with a certain downstream impairment in LDL metabolism in HepG2 cells.
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Chuan-Jue
authors.initials: CJ
authors.lastname: Cui
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Cheng-Gang
authors.initials: CG
authors.lastname: Zhu
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Du
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Na-Qiong
authors.initials: NQ
authors.lastname: Wu
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Yuan-Lin
authors.initials: YL
authors.lastname: Guo
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Rui-Xia
authors.initials: RX
authors.lastname: Xu
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Dyslipidemia, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Li
mesh_terms: D002097:C-Reactive Protein / Q000378:metabolism*; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011973:Receptors, LDL; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9
keywords: C-reactive protein; mitogen-activated protein kinase; pro-protein convertase subtilisin/kexin type 9