Neurosteroid transport by the organic solute transporter OSTα–OSTβ

Abstract

J. Neurochem. (2010) 115, 220–233. Abstract A variety of steroids, including pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulfate (DHEAS) are synthesized by specific brain cells, and are then delivered to their target sites, where they exert potent effects on neuronal excitability. The present results demonstrate that [3H]DHEAS and [3H]PREGS are relatively high affinity substrates for the organic solute transporter, OSTα–OSTβ, and that the two proteins that constitute this transporter are selectively localized to steroidogenic cells in the cerebellum and hippocampus, namely the Purkinje cells and cells in the cornu ammonis region in both mouse and human brain. Analysis of Ostα and Ostβ mRNA levels in mouse Purkinje and hippocampal cells isolated via laser capture microdissection supported these findings. In addition, Ostα‐deficient mice exhibited changes in serum DHEA and DHEAS levels, and in tissue distribution of administered [3H]DHEAS. OSTα and OSTβ proteins were also localized to the zona reticularis of human adrenal gland, the major region for DHEAS production in the periphery. These results demonstrate that OSTα–OSTβ is localized to steroidogenic cells of the brain and adrenal gland, and that it modulates DHEA/DHEAS homeostasis, suggesting that it may contribute to neurosteroid action.

Bile Formation and Secretion

“…In addition to bile salts, OSTα-OSTβ transports sterols conjugated with sulphate or glucuronic acid, including DHEAS, estrone-3-sulfate, digoxin, and prostaglandin E2 (45). Unconjugated sterols do not seem to be substrates (inhibitors) for OSTα-OSTβ (153). Both subunits of OSTα-OSTβ are highly regulated by bile salts via FXR response elements.…”

FXR agonist GW4064 increases plasma glucocorticoid levels in C57BL/6 mice

“…Data are expressed as fold compared to vehicle control and represent means + SEM of 8 mice per group. studies have suggested that OSTbeta is able to facilitate the transport of sulfated corticosterone (Fang et al, 2010). The increase in OSTbeta expression might therefore be the primary mechanism by which GW4064 increases plasma corticosterone levels.…”

Intestinal transport and metabolism of bile acids

“…But the in vivo phenotype was complex, where loss of IBABP was associated with reduced hepatic cholesterol 7alpha-hydroxylase (Cyp7a1) expression and increased fecal bile acid excretion widely expressed and is abundant in tissues important for steroid homeostasis ( 88 ). Because OST ␣ -OST ␤ also transports endogenous small molecules such as prostaglandins, neurosteroids, and steroid sulfates ( 109,110 ), it is possible that the intestinal adaptation is a response to alterations in transport of a non-bile acid substrate. For example, in vitro studies have shown that OST ␣ -OST ␤ can transport prostaglandin E2, which is important for regeneration of epithelial crypts following intestinal injury ( 111,112 ).…”