化物改变TGF-β信号传递,并诱导肥胖和癌症
Xiaochun Yang1, Krishanu Bhowmick1, Shuyun Rao2
1Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
化脱酶2 (ALDH2) 缺乏会使脂肪肝疾病 (MASH) 恶化. 针对SPTBN1,一种被有毒化物修饰的蛋白质,为抗击MASH和纤维化提供了一种新的治疗策略.
科学领域:
- 生物化学 生物化学
- 肝病学 肝病学是一种肝病学.
- 代谢疾病 代谢疾病
背景情况:
- 与代谢功能障碍相关的脂肪性肝病 (MASLD) 和脂肪性肝炎 (MASH) 影响全球超过三分之一的人口.
- 功能性降低的甲基脱酶2 (ALDH2) 加剧了MASH,影响全球约5.6亿人.
- 目前针对MASH进展为肝癌的治疗方法不足,需要新的治疗途径.
研究的目的:
- 调查内源性化物和SPTBN1在MASH和代谢综合征的发病过程中的作用.
- 探索SPTBN1作为MASH及其相关并发症的潜在治疗点.
主要方法:
- 使用Aldh2淘汰赛 (Aldh2-/-) 和Aldh2-/-Sptbn1+/-小鼠来模拟人类代谢综合征和MASH.
- 研究了转化生长因子β (TGF-β) 信号通路失调的机制,通过4-hydroxynonenal (4-HNE) 修改SPTBN1.
- 使用小干扰RNA (siRNA) 准SPTBN1并评估其在人类MASH模型和小鼠中的治疗疗效.
主要成果:
- Aldh2-/-和Aldh2-/-Sptbn1+/-小鼠表现出与人类代谢综合征和MASH一致的表型,具有像4-HNE这样的内源性化物升高.
- 鉴定出SPTBN1的4-HNE修饰是驱动异常TGF-β/SMAD3信号的关键机制,导致亲纤维和亲瘤变化.
- 在人类模型中,SPTBN1的治疗抑制成功地阻断了MASH和纤维化,并在Aldh2-/-小鼠中改善了葡萄糖代谢.
结论:
- SPTBN1是有毒化物诱导的MASH和纤维化发展的关键调解者.
- 向SPTBN1代表了管理MASH,肝纤维化和代谢功能障碍的有希望的治疗策略.
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