LAUSR

Aldosterone is considered to be a link between hypertension and obesity; obese individuals have high serum levels of both very low-density lipoprotein (VLDL) and sphingosine-1-phosphate (S1P). VLDL has been shown to stimulate aldosterone production in multiple zona glomerulosa cell models. S1P is transported in blood bound to lipoproteins such as VLDL, low-density lipoprotein, and high-density lipoprotein (HDL); the VLDL particle contains the highest levels of S1P. S1P in HDL has been shown to promote interactions between scavenger receptor class B, type I (SR-BI) and S1P receptor 1 (S1PR1). We hypothesized that like HDL, VLDL will signal through S1PRs upon binding to SR-BI; therefore, VLDL-induced aldosterone production will be inhibited by S1PR antagonists. Human adrenocortical cells (HAC15) were treated with VLDL and/or an S1PR1 antagonist (Ex26) for 24 h. The expression of steroidogenic genes and aldosterone production were monitored by qRT-PCR and radioimmunoassay, respectively. Ex26 inhibited VLDL-induced increases in CYP11B2 (22-fold) and StAR (1.5-fold) expression by 43% and 10%, respectively. Ex26 had no effect on VLDL-stimulated increase in NR4A1 expression. In addition, the VLDL-induced 5-fold increase in aldosterone levels was significantly inhibited by Ex26 (36%). Our results indicate that like HDL, VLDL likely signals by binding to SR-BI and activating S1PR1, such that an S1PR1 antagonist reduces VLDL-induced aldosterone production. Further investigation into these steroidogenic signaling pathways is warranted and may lead to the identification of therapeutic targets such as S1PR1 to potentially treat obesity-associated hypertension.