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随着代谢功能障碍相关的脂肪肝炎的组织学严重程度,肝脏葡萄糖的产生会增加
Silvia Sabatini1, Partho Sen2, Fabrizia Carli1
1Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy.
Cell reports. Medicine
|November 20, 2024
概括
与代谢功能障碍相关的脂肪性肝病 (MASLD) 和脂肪性肝炎 (MASH) 增加了纤维化和炎症的肝糖产量 (HGP),有助于胰岛素抵抗和2型糖尿病风险.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 代谢疾病 代谢疾病
- 内分泌学 在内分泌学.
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) 越来越普遍,并且与2型糖尿病 (T2D) 密切相关.
- 患有MASLD的患者经常表现出胰岛素抵抗 (IR) 和高血糖症,但肝脏葡萄糖生产 (HGP) 在疾病进展中的作用仍然不清楚.
- 了解将MASLD/MASH与高血糖和T2D联系在一起的机制对于开发向疗法至关重要.
研究的目的:
- 在人类队列中调查MASLD/MASH严重程度与肝脏葡萄糖 (HGP) 生产之间的关系.
- 阐明MASH中改变的HGP背后的代谢途径和分子机制.
- 确定导致高血糖和T2D风险增加的MASH患者的因素.
主要方法:
- 利用稳定同位素输液技术 (6,6-H2糖,U-H5糖醇) 来量化组织学证实MASLD/MASH.患者的HGP.
- 采用肝脏特定的基因组规模代谢模型 (GEMs) 来分析葡萄糖生成和代谢流.
- 与纤维化阶段和T2D状态相关的关键胰岛素信号通路组件 (IRS1,IRS2,AKT2) 的评估基因表达.
主要成果:
- 标志物测量HGP在MASH患者肝纤维化和炎症中显著升高,但不仅仅是由于脂肪酸.
- 增加的HGP与脂解和胰岛素抵抗的标志物相关.
- 对GEM的分析显示,由于乳酸,甘油和自由脂肪酸 (FFAs) 的摄入量增加,导致葡萄糖生成率升高.
- 在MASH中观察到胰岛素作用基因 (IRS1,IRS2,AKT2) 的减少表达,MASH患有晚期纤维化 (F2-F4),不论T2D状态如何.
结论:
- 肝脏葡萄糖产量增加,脂溶和胰岛素抵抗是MASH中的关键代谢变化.
- 这些发现为MASH患者观察到的高血糖症和2型糖尿病风险增加提供了机械洞察力.
- 准HGP,脂解或胰岛素信号通路可能为管理MASH相关的代谢并发症提供治疗策略.
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