期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 20, 期 12, 页码 2374-2383出版社
WILEY
DOI: 10.1111/jcmm.12931
关键词
C-reactive protein; pro-protein convertase subtilisin/kexin type 9; mitogen-activated protein kinase
资金
- National Natural Science Foundation of China [81070171, 81241121]
- Specialized Research Fund for the Doctoral Program of Higher Education of China [20111106110013]
- Capital Special Foundation of Clinical Application Research [Z121107001012015]
- Capital Health Development Fund [2011400302, 201614035]
- Beijing Natural Science Foundation [7131014]
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 mu g/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 1 alpha (HNF1 alpha) 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-HNF1 alpha pathway, with a certain downstream impairment in LDL metabolism in HepG2 cells.
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