Gain of pancreatic beta cell-specific SCD1 improves glucose homeostasis by maintaining functional beta cell mass under metabolic stress

IF 8.4 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetologia Pub Date : 2024-12-18 DOI:10.1007/s00125-024-06343-w
Wenyue Yin, Suyun Zou, Min Sha, Liangjun Sun, Haoqiang Gong, Can Xiong, Xinyue Huang, Jianan Wang, Yuhan Zhang, Xirui Li, Jin Liang, Xiaoai Chang, Shusen Wang, Dongming Su, Wanhua Guo, Yaqin Zhang, Tijun Wu, Fang Chen
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Abstract

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

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目的/假说关键的胰腺β细胞转录因子v-maf肌肉神经纤维肉瘤癌基因同源物A(MafA)对维持成熟β细胞的功能和表型至关重要。当β细胞长期暴露于高血糖(即葡萄糖毒性)等致糖尿病应激时,MafA的表达水平和/或活性就会降低。减少β细胞中MafA损失的干预目标和辅助疗法可为有效治疗糖尿病提供证据。在这项研究中,我们旨在研究硬脂酰-CoA 去饱和酶 1(SCD1)在稳定 MafA 表达和活性以维持功能性 beta 细胞质量方面的功能,从而抑制 2 型糖尿病的发展。方法:分析 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的胰岛中 SCD1 的表达水平。为了研究SCD1在β细胞功能和特性中的作用,研究人员制作了胰腺β细胞特异性SCD1基因敲除(βSCD1KI)小鼠。我们在 MIN6 和 HEK293A 细胞中检测了 SCD1 和 MafA 之间的蛋白间相互作用。结果与健康对照组相比,SCD1在2型糖尿病患者的β细胞中以及在HFD喂养的小鼠和db/db小鼠的β细胞中表达减少,这归因于葡萄糖毒性诱导的Scd1启动子组蛋白去乙酰化。在 HFD 诱导的糖尿病小鼠模型中,SCD1 在β细胞中的功能增益改善了胰岛素缺乏、葡萄糖不耐受和β细胞的去分化/转分化。从机理上讲,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MafA-HRD1的相互作用稳定核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 细胞中葡萄糖毒性介导的氧化应激。结论/解释我们的研究结果表明,SCD1 以依赖和不依赖去饱和酶的方式稳定了β细胞的 MafA,从而改善了代谢应激下的葡萄糖稳态。这为治疗糖尿病的精准医疗提供了一个潜在的新靶点。
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来源期刊
Diabetologia
Diabetologia 医学-内分泌学与代谢
CiteScore
18.10
自引率
2.40%
发文量
193
审稿时长
1 months
期刊介绍: Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
期刊最新文献
Correction: 60th EASD Annual Meeting of the European Association for the Study of Diabetes, Madrid, Spain, 9-13 September 2024. 'Average glucose and HbA1c display a nonlinear and variable relationship: implications for clinical practice'. Glycaemic control is still central in the hierarchy of priorities in type 2 diabetes management. Lifetime history of gestational diabetes and cognitive function in parous women in midlife. Is glycaemic control still central in the hierarchy of priorities in type 2 diabetes management? The way forward is to combine glucose control and the prevention of cardiorenal complications. Exposure to antibiotics and risk of latent autoimmune diabetes in adults and type 2 diabetes: results from a Swedish case-control study (ESTRID) and the Norwegian HUNT study.
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