Role of dehydroepiandrosterone in high-density lipoprotein-mediated vasodilation and in adipose tissue steroid biosynthesis

Dehydroepiandrosterone (DHEA) and its sulfate ester DHEA sulfate (DHEAS) are the most abundant steroid hormones in the circulation. These prohormones, secreted by the adrenal glands, are important precursors of biologically active androgens and estrogens. Adipose tissue is an important site for estrogen synthesis after menopause, when all estrogens are produced from hormone precursors in peripheral tissues. In the circulation, DHEA exists also as fatty acyl esters. These lipophilic derivatives of DHEA are transported by circulating lipoprotein particles. DHEA and high-density lipoprotein (HDL) both improve endothelial function. The aims of the present thesis were to study the role of DHEA fatty acyl esters in the HDL-mediated vasodilation, to study the cellular uptake and metabolism of HDL-associated DHEA fatty acyl esters in endothelial cells, and to investigate the metabolism of DHEAS in female adipose tissue. The role of DHEA fatty acyl esters in HDL-mediated vasodilation was studied in isolated rat arterial rings. DHEA fatty acyl ester-enriched human HDL showed a stronger vasodilatory effect compared to native HDL. This relaxation was mediated by HDL receptor, scavenger receptor class B, type I (SR-BI), and was partly dependent on the function of endothelial nitric oxide synthase. The metabolism of DHEA fatty acyl esters was studied in human endothelial cells. These cells were able to internalize and slowly hydrolyze HDL-associated DHEA fatty acyl esters and to further secrete the liberated free DHEA from the cells. In abdominal subcutaneous and visceral adipose tissue obtained from pre- and postmenopausal women, steroid sulfatase activity was assessed by the conversion of DHEAS to DHEA, and mRNA expression of steroid-converting enzyme genes was quantified. Steroid sulfatase activity was higher in postmenopausal than in premenopausal women both in subcutaneous and in visceral adipose tissue. Visceral fat showed a higher sulfatase activity compared to subcutaneous fat. Three genes in the estradiol-producing pathway, aromatase, 17β-hydroxysteroid dehydrogenase type 12, and hormone-sensitive lipase, were more expressed in postmenopausal than in premenopausal adipose tissue. In conclusion, DHEA fatty acyl esters enhanced the vasodilatory effect of HDL, suggesting that DHEA esters, associated with HDL as cargos, may improve the antiatherogenic function of HDL and thus promote cardiovascular health. Endothelial cells were able to internalize and hydrolyze HDL-associated DHEA fatty acyl esters. The hydrolysis was slow and thus presumably not responsible for the rapid vasodilatory effect of DHEA ester-enriched HDL. Steroid sulfatase activity in adipose tissue was higher in postmenopausal compared to premenopausal women, suggesting that circulating DHEAS could be more efficiently hydrolyzed and utilized in postmenopausal adipose tissue for the formation of biologically active androgens and estrogens. Depot-differences in the sulfatase activity and the gene expression of steroid-converting enzymes suggest that steroid hormone metabolism may differ between subcutaneous and visceral adipose tissue.