MODY3相关蛋白HNF1α第249位丝氨酸突变导致小鼠葡萄糖代谢异常

发布时间：2018-08-24 07:38

【摘要】：肝细胞核因子1α(HNF1α)不仅是调节葡萄糖代谢的重要转录因子,还参与肝、胰等多个器官中蛋白质合成、物质代谢、增殖分化相关基因的表达调控。HNF1α突变或表达异常引发包括青少年糖尿病3型(maturity onset diabetes of young 3,MODY3)在内的多种代谢疾病。Ser249是HNF1α重要的功能位点,该位点受ATM蛋白激酶直接磷酸化修饰,并可能是ATM蛋白激酶影响葡萄糖代谢的效应靶点,也可能是共济失调毛细血管扩张症(ataxia telangiectasia,AT)患者糖代谢异常的致病靶点。为进一步研究Ser249磷酸化在体内的功能,本文构建人源野生型HNF1α转基因小鼠(WT小鼠)和HNF1αS249A转基因小鼠(S249A小鼠),对其基础代谢水平和葡萄糖代谢能力进行检测。相较于对照小鼠,S249A小鼠的多项基础代谢指标异常,WT小鼠未显示差异;但当小鼠接受刺激后,无论是注射葡萄糖,还是丙酮酸或胰岛素,相较于各自的对照小鼠,WT小鼠都表现出更强的反应性,而S249A小鼠的糖异生反应和胰岛素敏感性均未显示出差异。实时定量PCR结果表明,WT小鼠肝的多个糖代谢基因表达上调,但S249A小鼠肝中糖代谢基因上调幅度明显小于WT小鼠。本研究提示,HNF1αSer249突变导致小鼠糖代谢异常,可能与磷酸化修饰失调进而影响其转录活性有关。
[Abstract]:Hepatic nuclear factor-1 伪 (HNF1 伪) is not only an important transcription factor regulating glucose metabolism, but also involved in protein synthesis and substance metabolism in many organs, such as liver and pancreas. Regulation of expression of genes related to Proliferation and differentiation. Mutation or abnormal expression of HNF1 伪 causes many metabolic diseases, including juvenile diabetes mellitus type 3 (maturity onset diabetes of young 3 / MODY3. Ser249 is an important functional site of HNF1 伪, which is directly modified by ATM protein kinase phosphorylation. It may also be an effective target for ATM protein kinase to affect glucose metabolism, and may also be a pathogenic target for abnormal glucose metabolism in patients with ataxia capillary dilatation (ataxia telangiectasia,AT). In order to further study the function of Ser249 phosphorylation in vivo, human wild-type HNF1 伪 transgenic mice (WT mice) and HNF1 伪 S249A transgenic mice (S249A mice) were constructed. There was no significant difference in several basic metabolic indexes in WT mice compared with control mice, but when the mice were stimulated, either glucose, pyruvate or insulin were injected. Compared with control mice, WT mice showed stronger reactivity, while S249A mice showed no difference in glucose heterogenetic reaction and insulin sensitivity. The results of real-time quantitative PCR showed that the expression of many glucose metabolism genes was up-regulated in liver of WT mice, but the up-regulation of glucose metabolism genes in liver of S249A mice was significantly lower than that of WT mice. This study suggests that the mutation of HNF1 伪 Ser249 may lead to abnormal glucose metabolism in mice, which may be related to the disorder of phosphorylation modification and its transcriptional activity.
【作者单位】：军事医学科学院放射与辐射医学研究所生化与分子生物学研究室;河北农业大学;
【基金】：国家自然科学基金(No.31271267)资助~~
【分类号】：R587.1

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