出版社：American Society for Biochemistry and Molecular Biology
摘要：Paraoxonase-1 (PON1), an enzyme that metabolizes organophosphateinsecticides, is secreted by the liver and transported in theblood complexed to HDL. In humans and mice, low plasma levelsof PON1 have also been linked to the development of atherosclerosis.We previously reported that hepatic Pon1 expression was decreasedwhen C57BL/6J mice were fed a high-fat, high-cholesterol dietsupplemented with cholic acid (CA). In the current study, weused wild-type and farnesoid X receptor (FXR) null mice to demonstratethat this repression is dependent upon CA and FXR. PON1 mRNAlevels were also repressed when HepG2 cells, derived from ahuman hepatoma, were incubated with natural or highly specificsynthetic FXR agonists. In contrast, fibroblast growth factor-19(FGF-19) mRNA levels were greatly induced by these same FXRagonists. Furthermore, treatment of HepG2 cells with recombinanthuman FGF-19 significantly decreased PON1 mRNA levels. Finally,deletion studies revealed that the proximal –230 to –96bp region of the PON1 promoter contains regulatory element(s)necessary for promoter activity and bile acid repression. Thesedata demonstrate that human PON1 expression is repressed bybile acids through the actions of FXR and FGF-19.Supplementary key words gene regulation • high density lipoprotein • atherosclerosis • mouse • c-Jun N-terminal kinase • farnesoid X receptor • fibroblast growth factor-19
Abbreviations: CA, cholic acid; CDCA, chenodeoxycholic acid; CYP7A1, cholesterol 7-hydroxylase; FGF-19, fibroblast growth factor-19; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; HNF-4, hepatocyte nuclear factor 4; JNK, c-Jun N-terminal kinase; PON1, paraoxonase-1; RXR, retinoid X receptor; SHP, small heterodimer partner; SREBP-2, sterol-regulatory element binding protein-2
-hydroxylase; FGF-19, fibroblast growth factor-19; FGFR4, fibroblast growth factor receptor 4; FXR, farnesoid X receptor; HNF-4, hepatocyte nuclear factor 4; JNK, c-Jun N-terminal kinase; PON1, paraoxonase-1; RXR, retinoid X receptor; SHP, small heterodimer partner; SREBP-2, sterol-regulatory element binding protein-2
