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Acetylation of Hsp90 reverses dexamethasone-mediated inhibition of insulin secretion
Toxicology Letters ( IF 2.9 ) Pub Date : 2020-03-01 , DOI: 10.1016/j.toxlet.2019.11.022
Kecheng Zhu 1 , Yumei Zhang 2 , Juan Zhang 3 , Feiye Zhou 1 , Linlin Zhang 1 , Shushu Wang 1 , Qin Zhu 1 , Qianqian Liu 1 , Xiao Wang 1 , Libin Zhou 1
Affiliation  

The deleterious effects of glucocorticoids on glucose homeostasis limit their clinical use. There is substantial evidence demonstrating that islet function impaired by long-term glucocorticoids exposure is a core defect in the progression of impaired glucose tolerance to diabetes. The activity of heat-shock protein (Hsp) 90 is required to maintain the hormone-binding activity and stability of glucocorticoid receptor (GR). In the present study, Hsp90 inhibition by 17-DMAG counteracted dexamethasone-mediated inhibition of glucose-stimulated insulin secretion in isolated rat islets as well as expressions of neuropeptide Y (NPY) and somatostatin receptor 3 (SSTR3), two negative regulators of insulin secretion. Like 17-DMAG, both the pan-histone deacetylase (HDAC) inhibitor TSA and HDAC6 inhibitor Tubacin exhibited a similar action in protecting islet function against dexamethasone-induced injury, along with the downregulation of NPY and SSTR3 expressions. The hyperacetylation of Hsp90 by TSA and Tubacin disrupted its binding ability to GR and blocked dexamethasone-elicited nuclear translocation of GR in INS-1 β-cell lines. In addition, Tubacin treatment triggered the GR protein degradation through the ubiquitin-proteasome pathway. These findings suggest that Hsp90 acetylation by inhibiting HDAC6 activity may be a potential strategy to prevent the development of steroid diabetes mellitus via alleviating glucocorticoid-impaired islet function.

中文翻译:

Hsp90 的乙酰化逆转地塞米松介导的胰岛素分泌抑制

糖皮质激素对葡萄糖稳态的有害影响限制了它们的临床应用。有大量证据表明,长期接触糖皮质激素导致胰岛功能受损是糖耐量受损进展为糖尿病的核心缺陷。需要热休克蛋白 (Hsp) 90 的活性来维持糖皮质激素受体 (GR) 的激素结合活性和稳定性。在本研究中,17-DMAG 对 Hsp90 的抑制抵消了地塞米松介导的对离体大鼠胰岛葡萄糖刺激胰岛素分泌的抑制以及神经肽 Y (NPY) 和生长抑素受体 3 (SSTR3) 的表达,这两种胰岛素分泌的负调节因子. 像 17-DMAG,泛组蛋白去乙酰化酶 (HDAC) 抑制剂 TSA 和 HDAC6 抑制剂 Tubacin 在保护胰岛功能免受地塞米松诱导的损伤方面表现出相似的作用,同时下调 NPY 和 SSTR3 的表达。TSA 和 Tubacin 对 Hsp90 的过度乙酰化破坏了其与 GR 的结合能力,并阻断了地塞米松引发的 INS-1 β 细胞系中 GR 的核易位。此外,Tubacin 处理通过泛素-蛋白酶体途径触发 GR 蛋白降解。这些发现表明 Hsp90 乙酰化通过抑制 HDAC6 活性可能是通过减轻糖皮质激素受损的胰岛功能来预防类固醇糖尿病发展的潜在策略。TSA 和 Tubacin 对 Hsp90 的过度乙酰化破坏了其与 GR 的结合能力,并阻断了地塞米松引发的 INS-1 β 细胞系中 GR 的核易位。此外,Tubacin 处理通过泛素-蛋白酶体途径触发 GR 蛋白降解。这些发现表明 Hsp90 乙酰化通过抑制 HDAC6 活性可能是通过减轻糖皮质激素受损的胰岛功能来预防类固醇糖尿病发展的潜在策略。TSA 和 Tubacin 对 Hsp90 的过度乙酰化破坏了其与 GR 的结合能力,并阻断了地塞米松引发的 INS-1 β 细胞系中 GR 的核易位。此外,Tubacin 处理通过泛素-蛋白酶体途径触发 GR 蛋白降解。这些发现表明 Hsp90 乙酰化通过抑制 HDAC6 活性可能是通过减轻糖皮质激素受损的胰岛功能来预防类固醇糖尿病发展的潜在策略。
更新日期:2020-03-01
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