通过PRDM16稳定色脂肪生物发生的翻译后控制
Qiang Wang1, Huixia Li2, Kazuki Tajima3
1Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
Nature
|August 17, 2022
概括
研究人员确定CUL2-APPBP2是PRDM16蛋白稳定的关键调节者. 抑制这种E3结合酶可以促进色脂肪细胞的形成,从而提供一种新的抗代谢疾病的策略.
科学领域:
- 代谢疾病研究
- 脂肪组织生物学
- 蛋白质的调节
背景情况:
- 棕色和色的脂肪组织可以预防代谢疾病.
- 含PR域16 (PRDM16) 激活色脂肪细胞生物发生,使其成为治疗点.
- 人们对PRDM16蛋白的稳定性知之甚少.
研究的目的:
- 确定负责PRDM16蛋白质降解的ubiquitin E3连接酶.
- 研究这种E3链酶在新陈代谢健康和衰老中的作用.
- 确定这种途径是否可以抵消代谢功能障碍.
主要方法:
- 确定了CUL2-APPBP2作为PRDM16的泛素E3结合酶.
- 研究了CUL2-APPBP2抑制对PRDM16稳定性和色脂肪细胞生物生成的影响.
- 在老化的脂肪组织中分析CUL2-APPBP2表达.
- 在饮食诱导的肥胖小鼠模型中研究了脂细胞特异性CUL2-APPBP2缺失的影响.
主要成果:
- CUL2-APPBP2催化PRDM16的多化,使其成为降解的目标.
- 抑制CUL2-APPBP2可以延长PRDM16的半衰期,并促进色脂肪细胞的形成.
- 陈旧的脂肪组织显示CUL2-APPBP2升高,通过降解PRDM16抑制热生成.
- 在小鼠中,脂肪细胞特异性的CUL2-APPBP2删除改善了肥胖,葡萄糖不耐受,胰岛素耐药性和脂质失调.
结论:
- CUL2-APPBP2是PRDM16蛋白稳定性的关键负调节剂.
- 向CUL2-APPBP2提供了一个细胞自主策略来激活脂肪组织中的PRDM16通路.
- 这种方法有可能治疗与脂肪细胞功能受损相关的代谢疾病.
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