线粒体适应性丧失与代谢功能障碍相关脂肪性肝病中线粒体周转和结构的恶化有关。
Loss of mitochondrial adaptation associates with deterioration of mitochondrial turnover and structure in metabolic dysfunction-associated steatotic liver disease.
作者信息
Sarabhai Theresia, Kahl Sabine, Gancheva Sofiya, Mastrototaro Lucia, Dewidar Bedair, Pesta Dominik, Ratter-Rieck Jacqueline M, Bobrov Pavel, Jeruschke Kay, Esposito Irene, Schlensak Matthias, Roden Michael
机构信息
Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine-University, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, Neuherberg, Germany.
Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research at Heinrich-Heine-University, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, Neuherberg, Germany.
出版信息
Metabolism. 2024 Feb;151:155762. doi: 10.1016/j.metabol.2023.155762. Epub 2023 Dec 19.
BACKGROUND
Obesity and type 2 diabetes frequently have metabolic dysfunction-associated steatotic liver disease (MASLD) including steatohepatitis (MASH). In obesity, the liver may adapt its oxidative capacity, but the role of mitochondrial turnover in MASLD remains uncertain.
METHODS
This cross-sectional study compared individuals with class III obesity (n = 8/group) without (control, OBE CON; NAFLD activity score: 0.4 ± 0.1) or with steatosis (OBE MASL, 2.3 ± 0.4), or MASH (OBE MASH, 5.3 ± 0.3, p < 0.05 vs. other groups). Hepatic mitochondrial ultrastructure was assessed by transmission electron microscopy, mitochondrial respiration by high-resolution respirometry, biomarkers of mitochondrial quality control and endoplasmic reticulum (ER) stress by Western Blot.
RESULTS
Mitochondrial oxidative capacity was 31 % higher in OBE MASL, but 25 % lower in OBE MASH (p < 0.05 vs. OBE CON). OBE MASH showed ~1.5fold lower mitochondrial number, but ~1.2-1.5fold higher diameter and area (p < 0.001 vs. other groups). Biomarkers of autophagy (p62), mitophagy (PINK1, PARKIN), fission (DRP-1, FIS1) and fusion (MFN1/2, OPA1) were reduced in OBE MASH (p < 0.05 vs. OBE CON). OBE MASL showed lower p62, p-PARKIN/PARKIN, and p-DRP-1 (p < 0.05 vs. OBE CON). OBE MASL and MASH showed higher ER stress markers (PERK, ATF4, p-eIF2α-S51/eIF2α; p < 0.05 vs. OBE CON). Mitochondrial diameter associated inversely with fusion/fission biomarkers and with oxidative capacity, but positively with HO.
CONCLUSION
Humans with hepatic steatosis already exhibit impaired mitochondrial turnover, despite upregulated oxidative capacity, and evidence for ER stress. In MASH, oxidative stress likely mediates progressive decline of mitochondrial turnover, ultrastructure and respiration indicating that mitochondrial quality control is key for energy metabolism and may have potential for targeting MASH. ClinGovTrial:NCT01477957.
背景
肥胖和2型糖尿病常伴有代谢功能障碍相关脂肪性肝病（MASLD），包括脂肪性肝炎（MASH）。在肥胖状态下，肝脏可能会调整其氧化能力，但线粒体更新在MASLD中的作用仍不明确。
方法
这项横断面研究比较了III级肥胖个体（每组n = 8），分为无（对照组，OBE CON；NAFLD活动评分：0.4±0.1）、有脂肪变性（OBE MASL，2.3±0.4）或MASH（OBE MASH，5.3±0.3，与其他组相比p < 0.05）。通过透射电子显微镜评估肝脏线粒体超微结构，通过高分辨率呼吸测定法评估线粒体呼吸，通过蛋白质免疫印迹法评估线粒体质量控制和内质网（ER）应激的生物标志物。
结果
OBE MASL的线粒体氧化能力高31%，但OBE MASH低25%（与OBE CON相比p < 0.05）。OBE MASH的线粒体数量低约1.5倍，但直径和面积高约1.2 - 1.5倍（与其他组相比p < 0.001）。自噬（p62）、线粒体自噬（PINK1、PARKIN）、裂变（DRP - 1、FIS1）和融合（MFN1/2、OPA1）的生物标志物在OBE MASH中降低（与OBE CON相比p < 0.05）。OBE MASL的p62、p - PARKIN/PARKIN和p - DRP - 1较低（与OBE CON相比p < 0.05）。OBE MASL和MASH显示较高的ER应激标志物（PERK、ATF4、p - eIF2α - S51/eIF2α；与OBE CON相比p < 0.05）。线粒体直径与融合/裂变生物标志物及氧化能力呈负相关，但与HO呈正相关。
结论
患有肝脂肪变性的人尽管氧化能力上调，但已表现出线粒体更新受损及ER应激证据。在MASH中，氧化应激可能介导线粒体更新、超微结构和呼吸的逐渐下降，表明线粒体质量控制是能量代谢的关键，可能具有针对MASH的治疗潜力。临床政府试验：NCT01477957。
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