Aims/hypothesis

The key pancreatic beta cell transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA) is critical for the maintenance of mature beta cell function and phenotype. The expression levels and/or activities of MafA are reduced when beta cells are chronically exposed to diabetogenic stress, such as hyperglycaemia (i.e. glucotoxicity). Interventional targets and adjuvant therapies to abate MafA loss in beta cells may provide evidence to support the effective treatment of diabetes. In this study, we aimed to investigate the function of stearoyl-CoA desaturase 1 (SCD1) in the stabilisation of MafA expression and activity in order to maintain functional beta cell mass, with a view to suppressing the development of type 2 diabetes.

Methods

SCD1 expression levels were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. Pancreatic beta cell-specific Scd1 knockin (βSCD1KI) mice were generated to study the role of SCD1 in beta cell function and identity. The protein-to-protein interactions between SCD1 and MafA were detected in MIN6 and HEK293A cells. We used experiments including chromatin immunoprecipitation, cell-based ubiquitination assay and fatty acid composition analysis to investigate the specific molecular mechanism underlying the effect of SCD1 on the restoration of MafA and beta cell function under glucotoxic conditions.

Results

SCD1 expression was reduced in beta cells of humans with type 2 diabetes and in HFD-fed and db/db mice compared with healthy controls, which was attributed to glucotoxicity-induced Scd1 promoter histone deacetylation. Gain-of-function of SCD1 in beta cells improved insulin deficiency, glucose intolerance and beta cell dedifferentiation/transdifferentiation in the HFD-induced mouse model of diabetes. Mechanistically, SCD1 directly bound to the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and stabilised nuclear MafA through interrupting MafA–HRD1 interactions in mouse islets and MIN6 cells, which inhibited the ubiquitination-mediated degradation of MafA. Moreover, the products of SCD enzyme reactions (mainly oleic acid) also alleviated glucotoxicity-mediated oxidative stress in MIN6 cells.

Conclusions/interpretation

Our findings indicate that SCD1 stabilises beta cell MafA both in desaturase-dependent and -independent manners, thus improving glucose homeostasis under metabolic stress. This provides a potential novel target for precision medicine for the treatment of diabetes.

Graphical Abstract

中文翻译：

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胰腺 β 细胞特异性 SCD1 的获得通过在代谢应激下维持功能性 β 细胞质量来改善葡萄糖稳态

 目标/假设

关键的胰腺 β 细胞转录因子 v-maf 肌肉腱膜纤维肉瘤癌基因同源物 A （MafA） 对于维持成熟 β 细胞功能和表型至关重要。当 β 细胞长期暴露于致糖尿病应激（例如高血糖症（即糖毒性））时，MafA 的表达水平和/或活性会降低。减少 β 细胞中 MafA 丢失的干预靶点和辅助疗法可能提供支持糖尿病有效治疗的证据。在这项研究中，我们旨在研究硬脂酰辅酶 A 去饱和酶 1 （SCD1） 在稳定 MafA 表达和活性中的作用，以维持功能性 β 细胞质量，以抑制 2 型糖尿病的发展。

 方法

分析了从 2 型糖尿病患者、高血糖 db/db 小鼠和高脂饮食 （HFD） 诱导的糖尿病小鼠模型获得的胰岛中的 SCD1 表达水平。生成胰腺 β 细胞特异性 Scd1 敲入 （βSCD1KI） 小鼠以研究 SCD1 在 β 细胞功能和身份中的作用。在 MIN6 和 HEK293A 细胞中检测到 SCD1 和 MafA 之间的蛋白间相互作用。我们使用包括染色质免疫沉淀、基于细胞的泛素化测定和脂肪酸组成分析在内的实验来研究 SCD1 在糖毒性条件下对 MafA 和 β 细胞功能恢复影响的特定分子机制。

 结果

与健康对照相比，SCD1 在 2 型糖尿病患者以及 HFD 喂养和 db/db 小鼠的 β 细胞中表达降低，这归因于糖毒性诱导的 Scd1 启动子组蛋白脱乙酰化。在 HFD 诱导的糖尿病小鼠模型中，β 细胞中 SCD1 的功能获得改善了胰岛素缺乏、葡萄糖耐量不良和 β 细胞去分化/转分化。从机制上讲，SCD1 直接与 E3 泛素连接酶 HMG-CoA 还原酶降解 1 （HRD1） 结合，并通过中断小鼠胰岛和 MIN6 细胞中的 MafA-HRD1 相互作用来稳定核 MafA，从而抑制泛素化介导的 MafA 降解。此外，SCD 酶反应的产物 （主要是油酸） 也减轻了 MIN6 细胞中糖毒性介导的氧化应激。

结论/解释

我们的研究结果表明，SCD1 以去饱和酶依赖性和非依赖性方式稳定 β 细胞 MafA，从而改善代谢应激下的葡萄糖稳态。这为糖尿病治疗的精准医学提供了一个潜在的新靶点。

 图形摘要