SAT040 Administration Of A DHCR24 Inhibitor Reduces The Excessive Adrenal Steroidogenesis In db/db Mice Through Effects The Alteration Of Intracellular Cholesterol Metabolism

Abstract

Abstract Disclosure: R. Kamigaki: None. H. Kameda: None. Y. Shibayama: None. H. Nomoto: None. K. Cho: None. A. Nakamura: None. S. Jin: None. K. Matoba: None. H. Miyoshi: None. T. Atsumi: None. Background and purpose: The circulating cortisol concentrations of patients with type 2 diabetes are high, suggesting that cortisol may be involved in diabetic complications. It has also been reported that the db/db mouse, a model of obesity and type 2 diabetes, has high circulating concentrations of steroid hormones. However, the mechanisms involved are unclear. In our previous study, we found that the expression of DHCR24, an enzyme that converts desmosterol (DES) to cholesterol (Chol) as part of de novo cholesterol synthesis, is upregulated in the adrenal glands of db/db mice. In the present study, we aimed to determine the effects of a DHCR24 inhibitor on adrenal steroidogenesis in db/db mice. Methods: Eight-week-old male db/db and db/+ mice were allocated to two groups, which were administered a weekly intraperitoneal injection of a DHCR24 inhibitor (U18666A; 10 mg/kg; (U) or PBS (P). Blood samples and their adrenal glands were collected 4 weeks later. We then compared the blood glucose, body mass, adrenal DES content, adrenal Chol content, and serum corticosterone (B) between the two groups. Sterols were extracted from adrenal tissue using the Folch method, and their concentrations were measured following picolinyl derivatization using liquid chromatography tandem-mass spectrometry. Results: There were no significant differences in the blood glucose concentrations or body masses of the P and U groups of both db/+ and db/db mice. The adrenal DES/adrenal mass ratio was higher in the db/db U group than in the db/db P group (db/db P vs. db/db U vs. db/+ P vs. db/+ U: 16.0±4.3 vs. 98.4±73.2 vs. 42.9±8.6 vs. 124.9±64.6 ng/mg, respectively; p<0.05). The adrenal Chol/adrenal mass and serum B concentration were lower in the db/db U and db/+ P groups than in the db/db P group (db/db P vs. db/db U vs. db/+ P vs. db/+ U: 2.1±0.2 vs. 1.3±0.2 vs. 1.1±0.6 vs. 1.3±0.2 μg/mg; and 232.8±20.1 vs. 189.6±13.1 vs. 126.3±20.6 vs. 111.2±25.8 ng/mL; respectively; all p<0.05). Conclusion: DHCR24 inhibition reduces cholesterol production and steroid hormone synthesis in the adrenal glands of db/db mice. This implies that the abnormal adrenal cholesterol metabolism in db/db mice plays a role in the greater adrenal steroidogenesis in type 2 diabetes, and that adrenal cholesterol metabolism may represent a novel therapeutic target for the affected patients. Presentation: Saturday, June 17, 2023