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P46Shc抑制了线粒体ACAA2硫酶,在衰老的肝脏中加剧了线粒体损伤和炎症

Yuan Li¹, Weiguo Fan¹, Tzu-Han Lo¹

¹Division of Gastroenterology and Hepatology, Stanford University, Stanford, California; Palo Alto VA Medical Center, Palo Alto, California.

The American journal of pathology

|December 29, 2024

概括

在衰老过程中Shc异形p46Shc的诱导会损害线粒体功能和脂质代谢,在代谢功能障碍相关的脂肪肝炎 (MASH) 中恶化肝损伤. 向Shc可能为MASH提供治疗策略.

科学领域:

线粒体生物学线粒体生物学
代谢性疾病研究研究.
细胞信号通道是细胞信号通道.

背景情况:

线粒体功能障碍是代谢功能障碍相关的脂肪肝炎 (MASH) 的关键驱动因素.
该Shc蛋白家族,特别是p46Shc异型,与与衰老相关的MASH进展有关.
在MASH中p46Shc在调节脂质代谢和线粒体功能的体内作用尚不清楚.

研究的目的:

为了研究p46Shc诱导在肝脏中的体内代谢后果.
在老化和MASH的小鼠模型中确定p46Shc对线粒体功能,脂质β氧化和氧化应激的影响.
探索针对MASH中的p46Shc的治疗潜力.

主要方法:

产生p46Shc诱导小鼠和衰老研究.
饮食干预措施包括和高脂肪,高果糖 (快餐) 饮食.
评估肝损伤,炎症,脂质过氧化,线粒体形态 (电子显微镜),氧气消耗 (Oroboros),β-基酸盐生产和反应性氧物种 (ROS) 的产生.
对主导负p46Shc对ACAA2活性和β-氧化的影响的评估.

主要成果:

p46Shc诱导在老年小鼠中加剧了肝损伤,炎症和脂质过氧化,特别是在快餐饮中.
线粒体表现出胀和异常的晶状体,氧气消耗减少,β-基酸盐的产生被抑制.
观察到ROS产量的增加,而主导负的p46Shc表达改善了β-氧化和减少了氧化应激.
p46Shc过度表达没有显著改变肝脏甘油三水平.

结论:

在衰老过程中,p46Shc的诱导抑制了乙-辅酶A乙转移酶2 (ACAA2),导致线粒体β-氧化减少和脂质过氧化增加.
维护线粒体β-氧化和生成对于预防MASH中肝损伤至关重要.
针对Shc介导的适应不良反应,为与衰老相关的MASH提供了一个有希望的治疗策略.

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