Androgen inactivation and steroid-converting enzyme expression in abdominal adipose tissue in men

Abstract

We examined 5a-dihydrotestosterone (5a-DHT) inactivation and the expression of several steroid-converting enzymes with a focus on aldoketoreductases 1C (AKR1C), especially AKR1C2, in abdominal adipose tissue in men. AKR1C2 is mainly involved in the conversion of the potent androgen 5a-DHT to its inactive forms 5a-androstane3a/b,17b-diol (3a/b-diol). Subcutaneous (s.c.) and omental (Om) adipose tissue biopsies were obtained from 21 morbidly obese men undergoing biliopancreatic derivation surgery and 11 lean to obese men undergoing general abdominal surgery. AKR1C2 mRNA and 5a-DHT inactivation were detected in both s.c. and Om adipose tissue. After incubation of preadipocytes with 5a-DHT, both 3a-diol and 3b-diol were produced through 3a/b-ketosteroid reductase (3a/b-HSD) activity. In preadipocyte cultures, 3a-reductase activity was significantly predominant over 3b-reductase activity in cells from both the s.c. and Om compartments. Expression levels of AKR1C1, AKR1C3 and of the androgen receptor were significantly higher in s.c. versus Om adipose tissue while mRNA levels of 17b-HSD-2 (hydroxysteroid dehydrogenase type 2) and 3(a/b)-hydroxysteroid epimerase were significantly higher in Om fat. 3a/b-HSD activity was mainly detected in the cytosolic fraction, suggesting that AKR1C may be responsible for this reaction. Experiments with isoform-specific AKR1C inhibitors in preadipocytes showed that AKR1C2 inhibition significantly decreased 3a-HSD and 3b-HSD activities (3a-HSD: 30G24% of control for s.c. and 32G9% of control for Om, 3b-HSD: 44G12% of control for s.c.). When cells were incubated with both AKR1C2 and AKR1C3 inhibitors, no significant additional inhibition was observed. 5a-DHT inactivation was significantly higher in mature adipocytes compared with preadipocyte cultures in s.c. adipose tissue, as expressed per microgram total protein (755G830 versus 245G151 fmol 3a/b-diol per mg protein over 24 h, P!0 . 05 nZ10 cultures). 5a-DHT inactivation measured in tissue homogenates was significantly higher in the s.c. depot compared with Om fat (117G39 versus 79G 38 fmol 3a/b-diol per mg prot over 24 h, P!0 . 0001). On the other hand, Om 3a/b-HSD activity was significantly higher in obese men (body mass index (BMI)R30 kg/m 2 ) compared with lean and overweight men (84G37 versus 52G30 fmol 3a/b-diol per mg protein over 24 h, P!0 . 03). No difference was found in s.c. 3a/b-HSD activity between these groups. Positive correlations were found between s.c. 5a-DHT inactivation rate and circulating levels of the androgen metabolites androsterone-glucuronide (rZ0 . 41, P!0 . 02) and 3a-diol-glucuronide (rZ0 . 38, P!0 . 03) and with the adrenal precursor androstenedione (rZ0 . 42, P!0 . 02). In conclusion, androgen inactivation was detected in abdominal adipose tissue in men, with higher 3a/b-HSD activity in the s.c. versus Om depot. Higher Om 5a-DHT inactivation rates were found in obese compared with lean men. Further studies are required to elucidate whether local androgen inactivation in abdominal adipose tissue ...

Regulation of human aldoketoreductase 1C3 (AKR1C3) gene expression in the adipose tissue

“…Hence, if AKR1C3 is primarily expressed in fully matured adipocytes, the lower expression in adipose tissue from obese subjects with the metabolic syndrome could reflect a larger proportion of immature adipocytes in the sc adipose tissue. Several studies have reported a depot difference in AKR1C3 expression, with sc adipose tissue displaying the highest expression [12][13][14][15]. Our study expands on these findings by showing that AKR1C3 has the highest expression levels in sc adipose tissue when compared with 64 other human tissues.…”

“…5. As in previous studies [12][13][14][15], omental adipose tissue displayed a lower expression level than sc adipose tissue.…”

“…Furthermore, AKR1C3 expression correlated with leptin levels and expression was higher in enlarged adipocytes. AKR1C3 expression in adipose tissue has previously mainly been investigated in relation to its role in steroid hormone conversion [12,13,15,31]. However, to the best of our knowledge, a direct link between adipose tissue AKR1C3 expression and the metabolic syndrome has not been investigated.…”

“…Researchers including ourselves have previously shown that a number of genes display different expression levels between the subcutaneous (sc) and the visceral depots [9][10][11]. One gene which has been shown in several studies to be expressed at higher levels in sc adipose tissue is aldoketoreductase 1C3 (AKR1C3; also known as type 5 17β-hydroxysteroid dehydrogenase; 17β-HSD-5) [12][13][14][15]. AKR1C3 is a multifunctional enzyme that is able to metabolize a diverse array of substrates, including various types of hydroxysteroids [16,17].…”

Differential androgen and estrogen substrates specificity in the mouse and primates type 12 17β-hydroxysteroid dehydrogenase

“…Adipose tissue is now considered as an important endocrine organ, which is a major site for metabolism of sex steroids (Kershaw & Flier 2004, Blouin et al 2006) and interestingly, the retroperitoneal fat Figure 1 Amino acid sequence comparison of the mouse, human, and monkey 17b-HSD12 and 17b-HSD3. The amino acid sequences of the mouse 17b-HSD12 and 17b-HSD3 are aligned with their primate homologs.…”