A Potential Role for 5‐Androstene‐3β,7β,17β‐triol in Obesity and Metabolic Syndrome

Abstract

Metabolic syndrome is marked by perturbed glucocorticoid (GC) signaling, systemic inflammation, and altered immune status. Dehydroepiandrosterone (DHEA), a major circulating adrenal steroid and dietary supplement, demonstrates antiobesity, anti-inflammatory, GC-opposing and immune-modulating activity when administered to rodents. However, plasma DHEA levels failed to correlate with metabolic syndrome and oral replacement therapy provided only mild benefits to patients. Androstene-3β,7β,17β-triol (β-AET) an anti-inflammatory metabolite of DHEA, also exhibits GC-opposing and immune-modulating activity when administered to rodents. We hypothesized a role for β-AET in obesity. We now report that plasma levels of β-AET positively correlate with BMI in healthy men and women. Together with previous studies, the observations reported here may suggest a compensatory role for β-AET in preventing the development of metabolic syndrome. The β-AET structural core may provide the basis for novel pharmaceuticals to treat this disease.

A synthetic anti‐inflammatory sterol improves insulin sensitivity in insulin‐resistant obese impaired glucose tolerance subjects

“…HE3286 significantly increased serum adiponectin in insulin‐resistant, but not in insulin‐sensitive subjects compared to placebo. This action may be due, in part, to effects on the expression of 11β‐hydroxysteroid dehydrogenase (11β‐HSD1) by HE3286, a synthetic derivative of the antiglucocorticoid βAET . 11β‐HSD1 overexpression is reported to decrease adiponectin serum levels in obese subjects .…”

“…HE3286 (17α‐ethynylandrost‐5‐ene‐3β,7β,17β‐triol) is a chemical derivative of the natural mammalian sterol androst‐5‐ene‐3β,7β,17β‐triol (βAET). βAET exhibits anti‐inflammatory activity in rodent models , is elevated in plasma of obese subjects with normal glucose disposal, and may play a compensatory role in preventing development of metabolic syndrome . βAET lacks pharmaceutical suitability, because of poor oral bioavailability and the propensity for inactivation by oxidation with 17β‐hydroxysteroid dehydrogenase .…”

17α-Ethynyl-androst-5-ene-3β,7β,17Nicoletti1, Philippens2, Fagone3 et al. 2012Parkinson's DiseaseSelf Cite7260View full textAdd to dashboardCite

“…HE3286 is pharmacologically unrelated to glucocorticoids and sex steroids, and although anti-inflammatory, it is not immunosuppressive and has no apparent potential for systemic toxicity at pharmacologically relevant exposures in rodents and canines [13]. β AET is found naturally in picomolar concentrations in human plasma [14], but is virtually absent in rodents without exogenous DHEA administration. β AET is not orally bioavailable, and plasma concentrations in humans cannot be appreciably augmented by DHEA supplementation due to DHEA's unfavorable absorption and metabolism characteristics [15].…”

Pharmacology and immune modulating properties of 5-androstene-3β,7β,17β-triol, a DHEA metabolite in the human metabolome

“…␤AET is one of several DHEA metabolites with anti-inflammatory activity [29,45], noting that some of these metabolites are also susceptible to metabolism, and therefore may be further transformed in vivo into the active entities. Recent studies suggest natural roles for ␤AET in preserving bone mineral content [46] and preventing the development of metabolic syndrome [35]. In a placebo controlled clinical trial it was shown to lower cholesterol in normal human subjects [47] consistent with DHEA activity in dogs reported by MacEwen and Kurzman [48].…”

“…␤AET is metabolically derived from DHEA through reduction of the 17-ketone by 17␤-hydroxysteroid dehydrogenase (17␤-HSD) and oxidation at C-7, which occurs in certain tissues, such as brain, liver, gut, lymphoid organs, joints and adipose through the activity of CYP3A [26] and CYP7B [19,32,33]. Human metabolic pathways do not favor the formation of highly oxidized DHEA metabolites [26], which are thus collectively present in low nanomolar concentrations in human circulation [34,35]. Other investigators have shown that they are not metabolized into sex steroids [36] and are not ligands for the peroxisome proliferator activated receptor [18].…”