Padelli Maël, Hamelin Jocelyne, Desterke Christophe, Sebagh Mylène, Saffroy Raphael, Sanchez Claudio Garcia, Coilly Audrey, Duclos-Vallée Jean-Charles, Samuel Didier, Lemoine Antoinette
Service de Biochimie et Oncogénétique, Hôpital Paul Brousse, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris Saclay, 94800 Villejuif, France.
Faculté de Médecine du Kremlin Bicêtre, Université Paris-Saclay, INSERM UMRS-1310, 94276 Le Kremlin-Bicêtre, France.
Int J Mol Sci. 2025 Jul 30;26(15):7373. doi: 10.3390/ijms26157373.
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, projected to affect 55% globally by 2040. Up to one-third of NAFLD patients develop non-alcoholic steatohepatitis (NASH), with 40% progressing to fibrosis. However, there are currently few reliable tools to predict disease progression. Impaired mitochondrial dynamics, characterized by dysregulated fission, fusion, and mitophagy, have emerged as key events in NAFLD pathophysiology, contributing to hepatocyte death and inflammation. This study explored the transition from steatosis to NASH through transcriptomic analyses, including data from patients with steatosis and those with NASH at different fibrosis stages. By identifying a transcriptomic signature associated with disease progression, the study revealed increased expression of genes involved in mitochondrial dynamics in NASH compared to steatosis and during NASH-related fibrosis. Histological analyses highlighted the central role of Dynamin-related protein 1 (Drp1), a dynamin GTPase essential for mitochondrial fission and mitophagy. In human liver biopsies, Drp1 expression progressively increased from NAFLD to NASH and NASH-related fibrosis and cirrhosis, predominantly in Kupffer cells. These finding suggest Drp1 is a potential driver of the transition to more severe liver damage, making it a promising biomarker for NASH development and progression and a potential therapeutic target in metabolic disorders.
非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病，预计到2040年全球将有55%的人受其影响。高达三分之一的NAFLD患者会发展为非酒精性脂肪性肝炎（NASH），其中40%会进展为肝纤维化。然而，目前几乎没有可靠的工具来预测疾病进展。线粒体动力学受损，其特征为裂变、融合和线粒体自噬失调，已成为NAFLD病理生理学中的关键事件，导致肝细胞死亡和炎症。本研究通过转录组分析探索了从脂肪变性到NASH的转变，分析数据包括来自不同纤维化阶段的脂肪变性患者和NASH患者的数据。通过识别与疾病进展相关的转录组特征，该研究发现与脂肪变性相比，NASH以及NASH相关纤维化过程中参与线粒体动力学的基因表达增加。组织学分析突出了动力蛋白相关蛋白1（Drp1）的核心作用，Drp1是一种对线粒体裂变和线粒体自噬至关重要的动力蛋白GTP酶。在人类肝脏活检中，Drp1的表达从NAFLD到NASH以及NASH相关纤维化和肝硬化逐渐增加，主要在库普弗细胞中。这些发现表明，Drp1是向更严重肝损伤转变的潜在驱动因素，使其成为NASH发生和进展的有前景的生物标志物以及代谢紊乱的潜在治疗靶点。
