Paraoxonase 1 deficiency in mice is associated with reduced steroid biosynthesis: effects on HDL binding, cholesteryl ester accumulation and scavenger receptor type BI expression.
OBJECTIVE
Selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE) is considered as the major source of cholesterol for production of steroids in the adrenal gland in rodents. As paraoxonase 1 (PON1) is an HDL-associated lipo-lactonase that has been shown to increase binding of HDL to macrophages, we used PON1 knock-out (PON1KO) mice to test the possible role of PON1 in corticosterone (CS) biosynthesis.


RESULTS
PON1 deficiency was associated with reduced serum CS concentration. Adrenal glands obtained from PON1KO mice had significantly lower CE content compared to adrenals from C57Bl6 control mice. Binding of HDL obtained from PON1KO mice to human adrenocortical carcinoma cell line was found to be significantly lower than that of control HDL, and was associated with decreased CS biosynthesis. Addition of purified PON1 to HDL from PON1KO mice increased HDL binding and CS synthesis. Furthermore, the expression of the HDL receptor, SR-BI, protein and mRNA, was reduced in adrenals from PON1KO mice compared to control mice. When challenged with low salt diet, PON1KO mice demonstrated an increase in adrenal SR-BI gene expression and in serum corticosterone which reached levels similar to those obtained in control mice.


CONCLUSIONS
PON1 regulates adrenal CS biosynthesis at two levels: (a) via an accessory role in HDL binding properties, and (b) a supportive role in SR-BI expression and CE supply to the cells.
Gamliel-Lazarovich
Aviva
A
Lipid Research Laboratory, The Rappaport Family Institute for Research in the Medical Sciences, Rappaport Faculty of Medicine, Technion and Rambam Medical Center, Haifa 31096, Israel.
Gantman
Anna
A
Shiner
Maayan
M
Coleman
Raymond
R
Aviram
Michael
M
Keidar
Shlomo
S
D000311:Adrenal Glands / Q000378:metabolism; D000818:Animals; D043303:Aryldialkylphosphatase / Q000172:deficiency*; D002788:Cholesterol Esters / Q000378:metabolism*; D003345:Corticosterone / Q000096:biosynthesis / Q000097:blood*; D004039:Diet, Sodium-Restricted; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis*; D014407:Tumor Cells, Cultured
D002788:Cholesterol Esters; D008075:Lipoproteins, HDL; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D043303:Aryldialkylphosphatase; D003345:Corticosterone