通过通过CREB信号传递促进肝脏葡萄糖生成,ZBED3会加剧高血糖症
Yuan-Yuan Luo1, Chang-Shun Ruan2, Fu-Zhen Zhao3
1Department of Endocrinology, Chongqing University Three Gorges Hospital, Chongqing, China; Chongqing Municipality Clinical Research Center for Endocrinology and Metabolic Diseases, Chongqing University Three Gorges Hospital, Chongqing, China; Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
Metabolism: clinical and experimental
|October 25, 2024
概括
含指BED域3 (ZBED3) 促进肝脏葡萄糖生成,这是糖尿病的一个关键过程. 这一发现突出了ZBED3作为糖尿病进展的关键调节者,提供了潜在的治疗点.
科学领域:
- 代谢性疾病是一种代谢性疾病.
- 分子生物学分子生物学
- 遗传学 是一个遗传学.
背景情况:
- 肝脏葡萄糖产量升高 (HGP) 是糖尿病的标志,由肝脏葡萄糖代谢受损驱动.
- 肝脏葡萄糖生成的增加显著导致糖尿病的禁食高血糖症.
- 含指BED域3 (ZBED3) 是2型糖尿病 (T2DM) 的风险基因,SNP与禁食血糖水平相关.
研究的目的:
- 研究ZBED3在调节肝脏葡萄糖生成中的作用.
- 阐明参与ZBED3介导的肝脏葡萄糖生成调节的信号通路.
主要方法:
- 在胰岛素抵抗性肝脏模型中评估了ZBED3表达.
- 利用RNA-seq和生物信息学来识别ZBED3相关的调节HGP的途径.
- 操纵ZBED3表达在体外 (MPHs,HHL-5细胞) 和体内 (肝细胞特异性淘汰/过度表达小鼠,db/db小鼠).
- 采用免疫沉-质谱,共同免疫沉,GST-pulldown和双露西法酶记者测试来确定分子机制.
主要成果:
- 在胰岛素耐药性疾病模型的肝脏组织中,ZBED3的表达增加.
- 在葡萄糖刺激下,ZBED3促进了葡萄糖原性基因表达 (PGC1A,PCK1,G6PC) 并增加了HGP.
- 肝细胞特异性的ZBED3过度表达提高了肝脏葡萄糖生成率,而淘汰赛降低了肝脏葡萄糖生成率.
- 在db/db小鼠中ZBED3倒退减少了肝脏葡萄糖生成.
- ZBED3促进了PRMT5的核转移,影响了PRMT5介导的CREB酸化,并促进了HGP.
结论:
- 在促进肝脏葡萄糖生成方面,ZBED3发挥着至关重要的作用.
- 在糖尿病的进展中,ZBED3起到关键的调节作用.
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