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 H₂O₂.

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

中文翻译：

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线粒体适应能力的丧失与代谢功能障碍相关的脂肪肝病中线粒体周转和结构的恶化有关

背景

肥胖和 2 型糖尿病经常患有代谢功能障碍相关的脂肪肝病 (MASLD)，包括脂肪性肝炎 (MASH)。在肥胖症中，肝脏可能会调整其氧化能力，但线粒体周转在 MASLD 中的作用仍不确定。

方法

这项横断面研究比较了没有（对照、OBE CON；NAFLD 活动）的 III 级肥胖个体（n =8/组）评分：0.4±0.1）或伴有脂肪变性（OBE MASL，2.3±0.4），或 MASH（OBE MASH，5.3±0.3，p <0.05与其他群体相比）。通过透射电子显微镜评估肝线粒体超微结构，通过高分辨率呼​​吸测量法评估线粒体呼吸，通过Western Blot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 中的线粒体氧化能力高出 31%，但 OBE MASH 中的线粒体氧化能力低 25%（p <0.05 与 OBE CON 相比）。 OBE MASH 显示线粒体数量减少约 1.5 倍，但直径和面积增加约 1.2–1.5 倍（与其他组相比，p <0.001）。 OBE MASH 中自噬 (p62)、线粒体自噬 (PINK1、PARKIN)、裂变 (DRP-1、FIS1) 和融合 (MFN1/2、OPA1) 的生物标志物减少 (p.₂O₂ <0.05 vs. OBE CON)。 OBE MASL显示出较低的p62、p-PARKIN/PARKIN和p-DRP-1(与OBE CON相比，p＜0.05)。 OBE MASL 和 MASH 显示出更高的 ER 应激标记（PERK、ATF4、p-eIF2α-S51/eIF2α；与 OBE CON 相比，p<0.05）。线粒体直径与融合/裂变生物标志物和氧化能力呈负相关，但与 H

结论

患有肝脂肪变性的人尽管氧化能力上调并且存在内质网应激的证据，但线粒体周转率已受损。在 MASH 中，氧化应激可能会介导线粒体周转、超微结构和呼吸的逐渐下降，这表明线粒体质量控制是能量代谢的关键，并且可能具有靶向 MASH 的潜力。

ClinGov试验： NCT01477957