载体SLC39A5的遗传失活化改善了肥胖的环境中的肝功能和高血糖
Shek Man Chim1, Kristen Howell1, John Dronzek1
1Regeneron Genetics Center, New York, United States.
eLife
|December 13, 2024
概括
溶性载体家族39,成员5 (SLC39A5) 基因中的罕见变异会增加水平,并可能降低II型糖尿病的风险. 缺乏Slc39a5的小鼠表现出改善的代谢健康和减少的肝病,这表明SLC39A5是治疗点.
科学领域:
- 遗传学和新陈代谢
- 分子生物学分子生物学
- 内分泌学 在内分泌学.
背景情况:
- 在胰岛素分泌和葡萄糖平衡中起作用,补充剂可改善II型糖尿病 (T2D) 的血糖特征.
- 载体SLC30A8的功能丧失变体与降低T2D风险有关,但将与葡萄糖代谢联系在一起的确切机制尚不清楚.
研究的目的:
- 研究调节水平和代谢特征的基因之间的关系.
- 确定影响葡萄糖平衡和T2D风险的新型遗传标.
主要方法:
- 发现EHR队列的外体序列测序,以确定与水平和代谢特征相关的基因.
- 通过跨祖先元分析,分析SLC39A5中的功能丧失变体及其与T2D风险的关联.
- 产生和研究Slc39a5缺乏的小鼠,包括肝功能,葡萄糖代谢和非酒精性脂肪肝炎 (NASH) 进展的评估.
主要成果:
- 在SLC39A5中罕见的功能丧失变体与循环水平的增加有关.
- 跨祖先的元分析表明,SLC39A5功能丧失变体与T2D风险降低之间存在标称关联.
- 缺少Slc39a5的小鼠表现出改善的肝功能,在肥胖条件下降低高血糖,以及减弱的肝纤维化和炎症在饮食诱导的NASH中,与肝升高和激活AMPK/AKT信号相关.
结论:
- SLC39A5调节肝脏平衡,影响葡萄糖代谢和肝脏健康.
- 缺少SLC39A5可以防止饮食引起的肥胖和NASH.
- SLC39A5成为代谢功能障碍的潜在治疗标,包括T2D和非酒精性脂肪肝疾病 (NAFLD).
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