Curcumin as a potent and selective inhibitor of 11β-hydroxysteroid dehydrogenase 1: improving lipid profiles in high-fat-diet-treated rats

Guo-Xin Hu, Han Lin, Qing-Quan Lian, Shu-Hua Zhou, Jingjing Guo, Hong-Yu Zhou, Yanhui Chu, Ren-Shan Ge, Guo-Xin Hu, Han Lin, Qing-Quan Lian, Shu-Hua Zhou, Jingjing Guo, Hong-Yu Zhou, Yanhui Chu, Ren-Shan Ge

Abstract

Background: 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) activates glucocorticoid locally in liver and fat tissues to aggravate metabolic syndrome. 11β-HSD1 selective inhibitor can be used to treat metabolic syndrome. Curcumin and its derivatives as selective inhibitors of 11β-HSD1 have not been reported.

Methodology: Curcumin and its 12 derivatives were tested for their potencies of inhibitory effects on human and rat 11β-HSD1 with selectivity against 11β-HSD2. 200 mg/kg curcumin was gavaged to adult male Sprague-Dawley rats with high-fat-diet-induced metabolic syndrome for 2 months.

Results and conclusions: Curcumin exhibited inhibitory potency against human and rat 11β-HSD1 in intact cells with IC50 values of 2.29 and 5.79 µM, respectively, with selectivity against 11β-HSD2 (IC50, 14.56 and 11.92 µM). Curcumin was a competitive inhibitor of human and rat 11β-HSD1. Curcumin reduced serum glucose, cholesterol, triglyceride, low density lipoprotein levels in high-fat-diet-induced obese rats. Four curcumin derivatives had much higher potencies for Inhibition of 11β-HSD1. One of them is (1E,4E)-1,5-bis(thiophen-2-yl) penta-1,4-dien-3-one (compound 6), which had IC50 values of 93 and 184 nM for human and rat 11β-HSD1, respectively. Compound 6 did not inhibit human and rat kidney 11β-HSD2 at 100 µM. In conclusion, curcumin is effective for the treatment of metabolic syndrome and four novel curcumin derivatives had high potencies for inhibition of human 11β-HSD1 with selectivity against 11β-HSD2.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Interconversion of cortisol and cortisone…
Figure 1. Interconversion of cortisol and cortisone by two 11β-hydroxysteroid dehydrogenase (11β-HSD) isoforms.
11β-HSD1 catalyzes the conversion of cortisone into cortisol in the liver or fat tissues, and 11β-HSD2 catalyzes the conversion of cortisol into cortisone in kidney or colon tissues.
Figure 2. Structures of curcumin and its…
Figure 2. Structures of curcumin and its pentadienone analogues.
Ar = aryl group; n = carbon numbers, where n = 0, designating open chain pentadienone compound, and n = 2, 3 designating cyclopentadienone compound.
Figure 3. Dose-dependent inhibition on 11β-HSD1 in…
Figure 3. Dose-dependent inhibition on 11β-HSD1 in intact rat Leydig cells by curcumin (compound 1) and it derivatives.
Figure 4. Lineweaver–Burk plot of rat liver…
Figure 4. Lineweaver–Burk plot of rat liver microsomal 11β-HSD1 in the presence of compound 6.
1/V versus 1/[11DHC], V, velocity (pmol/mg protein⋅min); [11DHC], concentrations of 11DHC.
Figure 5. Serum glucose, total cholesterol, Tg,…
Figure 5. Serum glucose, total cholesterol, Tg, LDL, APOA1 and APOB in rats from normal diet control (CON), HFD diet (HFD) and HFD plus curcumin (CUR).
Male rats were administered with 200 mg/kg curcumin for 2 months. Mean ± SE, n = 10. Identical letter designates no significant difference between two groups at P

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