Background

Previously, we reported that Mof was highly expressed in α-cells, and its knockdown led to ameliorated fasting blood glucose (FBG) and glucose tolerance in non-diabetic mice, attributed by reduced total α-cell but enhanced prohormone convertase (PC)1/3-positive α-cell mass. However, how Mof and histone 4 lysine 16 acetylation (H4K16ac) control α-cell and whether Mof inhibition improves glucose handling in type 2 diabetes (T2DM) mice remain unknown.

Methods

Mof overexpression and chromatin immunoprecipitation sequence (ChIP-seq) based on H4K16ac were applied to determine the effect of Mof on α-cell transcriptional factors and underlying mechanism. Then we administrated mg149 to α-TC1-6 cell line, wild type, db/db and diet-induced obesity (DIO) mice to observe the impact of Mof inhibition in vitro and in vivo. In vitro, western blotting and TUNEL staining were used to examine α-cell apoptosis and function. In vivo, glucose tolerance, hormone levels, islet population, α-cell ratio and the co-staining of glucagon and PC1/3 or PC2 were examined.

Results

Mof activated α-cell-specific transcriptional network. ChIP-seq results indicated that H4K16ac targeted essential genes regulating α-cell differentiation and function. Mof activity inhibition in vitro caused impaired α-cell function and enhanced apoptosis. In vivo, it contributed to ameliorated glucose intolerance and islet dysfunction, characterized by decreased fasting glucagon and elevated post-challenge insulin levels in T2DM mice.

Conclusion

Mof regulates α-cell differentiation and function via acetylating H4K16ac and H4K16ac binding to Pax6 and Foxa2 promoters. Mof inhibition may be a potential interventional target for T2DM, which led to decreased α-cell ratio but increased PC1/3-positive α-cells.

中文翻译：

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Mof 乙酰转移酶抑制通过靶向胰腺 α 细胞改善 2 型糖尿病的葡萄糖耐受不良和胰岛功能障碍

 背景

此前，我们报道了 Mof 在 α 细胞中高表达，其敲低可改善非糖尿病小鼠的空腹血糖 (FBG) 和糖耐量，这归因于总 α 细胞减少但激素原转化酶 (PC) 增强1 /3-阳性α细胞团。然而，Mof 和组蛋白 4 赖氨酸 16 乙酰化 (H4K16ac) 如何控制 α 细胞以及 Mof 抑制是否改善 2 型糖尿病 (T2DM) 小鼠的葡萄糖处理仍不清楚。

 方法

应用 Mof 过表达和基于 H4K16ac 的染色质免疫沉淀序列 (ChIP-seq) 来确定 Mof 对 α 细胞转录因子的影响及其潜在机制。然后我们将mg149给予α-TC1-6细胞系、野生型、db/db和饮食诱导肥胖(DIO)小鼠，观察体外和体内Mof抑制的影响。在体外，使用蛋白质印迹和TUNEL染色来检查α细胞凋亡和功能。在体内，检查了葡萄糖耐量、激素水平、胰岛数量、α细胞比例以及胰高血糖素和PC1/3或PC2的共染色。

 结果

Mof 激活 α 细胞特异性转录网络。 ChIP-seq 结果表明 H4K16ac 靶向调节 α 细胞分化和功能的必需基因。体外 Mof 活性抑制会导致 α 细胞功能受损并增强细胞凋亡。在体内，它有助于改善 T2DM 小鼠的葡萄糖耐受不良和胰岛功能障碍，其特征是空腹胰高血糖素降低和攻击后胰岛素水平升高。

 结论

Mof 通过乙酰化 H4K16ac 和 H4K16ac 与 Pax6 和 Foxa2 启动子的结合来调节 α 细胞分化和功能。 Mof 抑制可能是 T2DM 的潜在干预靶点，它导致 α 细胞比例下降，但 PC1/3 阳性 α 细胞增加。