Vitamin D(3) auto-/paracrine system in rat brain relating to vitamin D(3) status in experimental type 2 diabetes mellitus

The Ukrainian Biochemical Journal Pub Date : 2024-04-25 DOI:10.15407/ubj96.02.038

I. Shymanskyi, O. Lisakovska, A. Khomenko, L. Yanitska, M. Veliky

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Abstract

Growing evidence suggests that vitamin D3 (D3, cholecalciferol) deficiency and impaired signaling of the hormonally active form of D3, 1α,25(OH)2D3 (1,25D3), through its cellular receptor (VDR) can be significant risk factors for the development of numerous multifactorial diseases, including diabetes. Our investigation was aimed at researching the D3 status in relation to the state of the D3 auto-/paracrine system in the brain and clarifying the effectiveness of the therapeutic use of D3 as a neuroprotective agent in experimental type 2 diabetes mellitus (T2DM). T2DM was induced in male Wistar rats by a combination of a high fat diet and a low dose of streptozotocin (25 mg/kg BW). Diabetic animals were treated with or without cholecalciferol (1,000 IU/kg BW, 30 days). The content of 25-hydroxyvitamin D3 (25D3) in blood serum and brain tissue was determined by ELISA. Analysis of mRNA expression of CYP24A1 and CYP27B1 genes was performed by RT-PCR. Protein levels of VDR, vitamin D3 binding protein (VDBP), CYP27B1 and CYP24A1 were investigated by Western blotting. A significant T2DM-associated decrease in the content of 25D3 in the blood serum was revealed, which correlated with a reduced content of this metabolite in the brain tissue. Impaired D3 status in animals with T2DM was accompanied by an increase in the levels of mRNA and protein of both 25D3 lα-hydroxylase (CYP27B1) and 1,25-hydroxyvitamin D3-24-hydroxylase (CYP24A1), which, respectively, provide local formation and degradation in the nervous tissue of the hormonally active form of D3 – 1,25D3. At the same time, a significant T2DM-induced down-regulation of the brain content of VDBP was shown. In addition, diabetes caused a slight increase in the protein expression of the VDR, through which the auto-/paracrine effects of 1,25D3 are realized in the brain. We have established a complete or partial corrective effect of cholecalciferol on D3 status, its bioavailability in the CNS and the level of protein expression of CYP27B1 and CYP24A1 in the brain of rats with T2DM. Abnormal D3 status in animals with T2DM was accompanied by compensatory changes in the expression of key components of the auto-/paracrine vitamin D3 system. Cholecalciferol was demonstrated to be partially effective in counteracting the impairments caused by T2DM. Keywords: 25-hydroxyvitamin D3, brain, type 2 diabetes, vitamin D3, vitamin D3 auto-/paracrine system

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实验性 2 型糖尿病大鼠脑内与维生素 D(3) 状态有关的维生素 D(3) 自体/旁分泌系统

越来越多的证据表明，维生素D3（D3，胆钙化醇）缺乏和D3的激素活性形式1α,25(OH)2D3（1,25D3）通过其细胞受体（VDR）发出的信号受损可能是导致包括糖尿病在内的多种多因素疾病的重要风险因素。我们的调查旨在研究 D3 状态与大脑中 D3 自体/旁分泌系统状态的关系，并阐明在实验性 2 型糖尿病（T2DM）中使用 D3 作为神经保护剂的治疗效果。雄性 Wistar 大鼠通过高脂肪饮食和低剂量链脲佐菌素（25 毫克/千克体重）诱发 T2DM。糖尿病动物接受或不接受胆钙化醇（1,000 IU/公斤体重，30 天）治疗。用酶联免疫吸附法测定血清和脑组织中 25- 羟维生素 D3（25D3）的含量。通过 RT-PCR 分析了 CYP24A1 和 CYP27B1 基因的 mRNA 表达。用 Western 印迹法检测了 VDR、维生素 D3 结合蛋白（VDBP）、CYP27B1 和 CYP24A1 的蛋白水平。结果显示，T2DM 导致血清中 25D3 的含量明显下降，这与脑组织中该代谢物含量的减少有关。25D3 lα-hydroxylase (CYP27B1)和 1,25-羟维生素 D3-24-hydroxylase (CYP24A1)的 mRNA 和蛋白质水平均升高，这两种酶分别负责在神经组织中形成和降解具有激素活性的 D3--1,25D3。与此同时，T2DM 诱导的脑内 VDBP 含量出现了明显的下调。此外，糖尿病还导致 VDR 蛋白表达量的轻微增加，而 1,25D3 在大脑中的自身/旁分泌效应正是通过 VDR 实现的。我们确定了胆钙化醇对 D3 状态、其在中枢神经系统中的生物利用率以及 CYP27B1 和 CYP24A1 在 T2DM 大鼠大脑中的蛋白表达水平的完全或部分纠正作用。T2DM 动物体内 D3 状态的异常伴随着自身/旁分泌维生素 D3 系统关键成分表达的代偿性变化。研究证明，胆钙化醇能部分有效地抵消T2DM造成的损伤。关键词25-羟基维生素D3、大脑、2型糖尿病、维生素D3、维生素D3自身/旁分泌系统

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The Ukrainian Biochemical Journal

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