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Activation and dephosphorylation of PPARgamma induce PCSK9 production
Author(s) -
Duan Yajun,
Chen Yuanli,
Han Jihong
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.656.15
Subject(s) - pcsk9 , dephosphorylation , ldl receptor , peroxisome proliferator activated receptor , phosphorylation , chemistry , receptor , endocrinology , medicine , microbiology and biotechnology , biology , cholesterol , biochemistry , lipoprotein , phosphatase
PCSK9 plays an important role in cholesterol homeostasis by enhancing the degradation of LDLR protein. PPARγ, a ligand activated transcriptional factor, has been shown to be atheroprotective. PPARγ can be phosphorylated by ERK1/2 and the phosphorylated status of PPARγ greatly impacts its biological activity. However, the interplay between PCSK9 and PPARγ/phosph‐PPARγ remains unknown. We observed that PPARγ ligands induced PCSK9 mRNA and protein expression in HepG2 cells. Inhibition of ERK1/2 induced while activation of ERK1/2 inhibited PCSK9 expression. Co‐treatment of PPARγ ligand and ERK1/2 inhibitor had no additive effect on the induction of PCSK9 expression. The induction of PCSK9 expression by ERK1/2 inhibitor was tightly linked to the dephosphorylation of PPARγ. In vivo, the administration of PPARγ ligand or ERK1/2 inhibitor alone increased PCSK9 expression in mouse liver but had no effect on PCSK9 secretion. However, the co‐administration of PPARγ ligand and ERK1/2 inhibitor enhanced both PCSK9 expression and secretion. Interestingly, the up‐regulation of PCSK9 expression by PPARγ ligand and/or ERK1/2 inhibitor was associated with the increased LDLR expression in the liver and the decreased LDL‐cholesterol levels in serum. Our study discloses a new mechanism involving in regulation of PCSG9 expression and may have implication in the development of strategies for PCSK9 expression and function.

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