| First Author | Mitić T | Year | 2013 |
| Journal | Biochem Pharmacol | Volume | 86 |
| Issue | 1 | Pages | 146-53 |
| PubMed ID | 23415904 | Mgi Jnum | J:199550 |
| Mgi Id | MGI:5503009 | Doi | 10.1016/j.bcp.2013.02.002 |
| Citation | Mitic T, et al. (2013) 11beta-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo. Biochem Pharmacol 86(1):146-53 |
| abstractText | 11beta-Hydroxysteroid dehydrogenase 1 (11betaHSD1; EC 1.1.1.146) generates active glucocorticoids from inert 11-keto metabolites. However, it can also metabolize alternative substrates, including 7beta-hydroxy- and 7-keto-cholesterol (7betaOHC, 7KC). This has been demonstrated in vitro but its consequences in vivo are uncertain. We used genetically modified mice to investigate the contribution of 11betaHSD1 to the balance of circulating levels of 7KC and 7betaOHC in vivo, and dissected in vitro the kinetics of the interactions between oxysterols and glucocorticoids for metabolism by the mouse enzyme. Circulating levels of 7KC and 7betaOHC in mice were 91.3+/-22.3 and 22.6+/-5.7 nM respectively, increasing to 1240+/-220 and 406+/-39 nM in ApoE(-/-) mice receiving atherogenic western diet. Disruption of 11betaHSD1 in mice increased (p<0.05) the 7KC/7betaOHC ratio in plasma (by 20%) and also in isolated microsomes (2 fold). The 7KC/7betaOHC ratio was similarly increased when NADPH generation was restricted by disruption of hexose-6-phosphate dehydrogenase. Reduction and oxidation of 7-oxysterols by murine 11betaHSD1 proceeded more slowly and substrate affinity was lower than for glucocorticoids. in vitro 7betaOHC was a competitive inhibitor of oxidation of corticosterone (Ki=0.9 muM), whereas 7KC only weakly inhibited reduction of 11-dehydrocorticosterone. However, supplementation of 7-oxysterols in cultured cells, secondary to cholesterol loading, preferentially slowed reduction of glucocorticoids, rather than oxidation. Thus, in mouse, 11betaHSD1 influenced the abundance and balance of circulating and tissue levels of 7betaOHC and 7KC, promoting reduction of 7KC. In health, 7-oxysterols are unlikely to regulate glucocorticoid metabolism. However, in hyperlipidaemia, 7-oxysterols may inhibit glucocorticoid metabolism and modulate signaling through corticosteroid receptors. |
