Todorovic Smilja, Milosevic Katarina, Milosevic Ana, Janjic Marija M, Sokanovic Srdjan J, Savic Danijela, Lavrnja Irena
Institute for Biological Research "Siniša Stanković" - National Institute of Republic of Serbia, Department for Neurobiology, University of Belgrade, Serbia.
Folia Neuropathol. 2025;63(2):148-156. doi: 10.5114/fn.2024.141376.
Dysregulations in cholesterol homeostasis contribute to the pathogenesis of multiple sclerosis (MS) and its best described animal model, experimental autoimmune encephalomyelitis (EAE). Cholesterol is an important component of myelin, which is necessary for signal transmission between neurons. Demyelination leads to the formation of oxysterols, degradation products of cholesterol that are ligands for nuclear liver X receptors (LXRs). Genes regulated by LXRs are involved in cholesterol efflux, absorption, transport, and excretion, which we investigated in this study. In this study, we detected changes in gene expression of Srebf1, Ldlr, Soat1, Abca1, Lrp1, and Npc1, all of which are important in the regulation of cholesterol homeostasis, during the course of EAE in male and female rats. In particular, differential expression of Srebf1, Ldlr, and Soat1 was observed in the spinal cord of male and female rats during EAE. Moreover, these genes are altered during EAE. In contrast, the expression of Abca1 and Lrp1 was significantly affected only by sex. In male animals, the expression of Npc1 is conspicuously reduced in EAE pathology. Thus, our study confirms the involvement of enzymes of cholesterol metabolism in the pathophysiology of EAE, with sex and disease progression affecting the expression of these genes. These findings may improve the understanding of neurodegenerative diseases associated with impaired lipid metabolism in the brain, such as MS/EAE.
胆固醇稳态失调促成了多发性硬化症（MS）及其最佳描述动物模型——实验性自身免疫性脑脊髓炎（EAE）的发病机制。胆固醇是髓磷脂的重要组成部分，而髓磷脂是神经元之间信号传递所必需的。脱髓鞘会导致氧化甾醇的形成，氧化甾醇是胆固醇的降解产物，是核肝X受体（LXRs）的配体。受LXRs调控的基因参与胆固醇外流、吸收、运输和排泄，我们在本研究中对其进行了调查。在本研究中，我们检测了雄性和雌性大鼠EAE病程中Srebf1、Ldlr、Soat1、Abca1、Lrp1和Npc1的基因表达变化，所有这些基因在胆固醇稳态调节中都很重要。特别是，在EAE期间，雄性和雌性大鼠脊髓中观察到Srebf1、Ldlr和Soat1的差异表达。此外，这些基因在EAE期间发生改变。相比之下，Abca1和Lrp1的表达仅受性别显著影响。在雄性动物中，Npc1的表达在EAE病理过程中明显降低。因此，我们的研究证实了胆固醇代谢酶参与EAE的病理生理学，性别和疾病进展会影响这些基因的表达。这些发现可能有助于加深对与大脑脂质代谢受损相关的神经退行性疾病（如MS/EAE）的理解。
