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通过抑制SREBP激活,HSD17B6延迟了2型糖尿病的发展
Fengxiang Wei1, Yan Gu2, Lizhi He2
1The Genetics Laboratory, Longgang District Maternity and Child Healthcare Hospital of Shenzhen City, Longgang District, Shenzhen, Guangdong, China; Urological Cancer Center for Research and Innovation (UCCRI), St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada; The Research Institute of St Joe's Hamilton, St Joseph's Hospital, Hamilton, ON L8N 4A6, Canada; Department of Surgery, McMaster University, Hamilton, ON L8S 4K1, Canada.
氧类固醇17-β脱酶6 (HSD17B6) 通过结合SREBP/SCAP/INSIG复合体来抑制SREBP信号传递. 这种作用改善了葡萄糖耐受性,并减少了与肥胖相关的2型糖尿病 (T2D) 的发展.
科学领域:
- 代谢过程中的代谢.
- 分子生物学分子生物学
- 内分泌学 在内分泌学.
背景情况:
- 这种SREBP/SCAP/INSIG复合体对于SREBP激活和新生脂质生成至关重要.
- 氧类固醇17-β脱酶6 (HSD17B6) 在SREBP激活中的作用尚不清楚.
研究的目的:
- 研究HSD17B6对SREBP激活的影响及其在代谢调节中的作用.
- 确定HSD17B6对SREBP信号传递的影响是否需要HSD17B6的酶活性.
主要方法:
- 通过在各种细胞系和初级肝细胞中使用SRE-luciferase记者来评估SREBP转录活性.
- 分析了HSD17B6及其突变体和SREBP/SCAP/INSIG复合体之间的相互作用.
- 在体内研究中使用了饮食诱导的肥胖小鼠和多基因2型糖尿病小鼠模型来评估HSD17B6对葡萄糖耐受性,肥胖和T2D的影响.
主要成果:
- HSD17B6直接与SREBP/SCAP/INSIG复合体结合,抑制了肝细胞和小鼠肝脏中的SREBP信号传递.
- 一个突变的HSD17B6,在雄激素代谢中有缺陷,保留了它抑制SREBP信号传递的能力,表明它独立于固醇氧化酶活性.
- 在肥胖小鼠中,肝脏HSD17B6表达改善了葡萄糖耐受性和降低了肝脏甘油三含量,而敲击则加剧了葡萄糖不耐受性.
- 在T2D小鼠中肝脏特异性的HSD17B6表达减弱了疾病的发展.
结论:
- HSD17B6通过与SREBP/SCAP/INSIG复合体相互作用来抑制SREBP的成熟,独立于其酶活性.
- HSD17B6增强了葡萄糖耐受性,并对抗肥胖引起的2型糖尿病.
- HSD17B6代表了2型糖尿病治疗的潜在治疗标.
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