Graindorge Paul-Henri, Paoli Justine, Yildirim Berivan, Morel Chloe, Herzine Ameziane, Collin Maud, Gallais Isabelle, Boucard Stephane, Pouyatos Benoît, Meyre David, Lagadic-Gossmann Dominique, Sergent Odile, Schroeder Henri, Grova Nathalie
UMR Inserm 1256 nGERE - Lorraine University, 9 Avenue de La Forêt de Haye, 54500, Vandœuvre-Lès-Nancy, France.
Plateforme animalerie - Orleans University, 1 Rue de Chartes, 45067, Orléans, France.
Sci Rep. 2025 Mar 27;15(1):10616. doi: 10.1038/s41598-025-94234-4.
Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is a chronic liver disease affecting 25% of the European population, with rising global incidence. Liver damage includes ballooning, steatosis, inflammation and fibrosis. Associated brain disorders include sleep, cognitive issues, anxiety, and depression. While neurological complications in advanced MASLD are well documented, early cerebral manifestations remain largely unexplored. This study aimed at developing an MASLD rat model to assess the onset of early brain damage, focusing on impairments of the circadian cycle rhythm and associated neuroinflammation. Sprague Dawley rats were divided into two groups: one received a high-fat, high-cholesterol (HFHC) diet for 90 days, while the other received a standard diet. Histological analysis showed significant hepatic steatosis, ballooning, and inflammation in the HFHC group (p < 0.01). These lesions correlated with elevated hepatic triglycerides (p < 0.01), increased Alanine Aminotransferase, Aspartate Aminotransferase, total cholesterol, and low-density lipoprotein, alongside decreased plasma high-density lipoprotein. Behavioural analysis using activity wheels revealed that the HFHC rats steadily maintained their activity level during the rest periods when compared with controls (p < 0.05). This behavioural alteration occurred alongside neuroinflammation, demonstrated by changes in the expression of 36 and 17 inflammatory mediators in the cerebellum and frontal cortex respectively. These changes were associated with an increase in the expression of glial cell markers (Aif1 and Gfap genes) and an increase in the number of microglial cells, affecting the frontal cortex and cerebellum differently. This rat model of early MASLD shows circadian rhythm disturbances, which could reflect sleep disorders in humans. These early brain disturbances specific to MASLD, which occur before the symptoms of liver disease become clinically apparent, could therefore be used as an early diagnosis marker for MASLD patients.
代谢功能障碍相关脂肪性肝病（MASLD）是一种慢性肝病，影响着25%的欧洲人口，且全球发病率呈上升趋势。肝脏损伤包括气球样变、脂肪变性、炎症和纤维化。相关的脑部疾病包括睡眠、认知问题、焦虑和抑郁。虽然晚期MASLD的神经并发症已有充分记录，但早期脑部表现仍 largely 未被探索。本研究旨在建立一个MASLD大鼠模型，以评估早期脑损伤的发生，重点关注昼夜节律周期的损害和相关的神经炎症。将Sprague Dawley大鼠分为两组：一组接受高脂、高胆固醇（HFHC）饮食90天，另一组接受标准饮食。组织学分析显示，HFHC组有明显的肝脏脂肪变性、气球样变和炎症（p < 0.01）。这些病变与肝脏甘油三酯升高（p < 0.01）、丙氨酸转氨酶、天冬氨酸转氨酶、总胆固醇和低密度脂蛋白增加以及血浆高密度脂蛋白降低相关。使用活动轮进行的行为分析显示，与对照组相比，HFHC大鼠在休息期间的活动水平稳定维持（p < 0.05）。这种行为改变与神经炎症同时发生，分别通过小脑和额叶皮质中36种和17种炎症介质表达的变化得以证明。这些变化与胶质细胞标志物（Aif1和Gfap基因）表达的增加以及小胶质细胞数量的增加相关，对额叶皮质和小脑的影响不同。这种早期MASLD大鼠模型显示出昼夜节律紊乱，这可能反映了人类的睡眠障碍。因此，这些在肝病症状临床上明显之前就出现的、MASLD特有的早期脑部紊乱，可作为MASLD患者的早期诊断标志物。
