Johnson Rabia, Shabalala Samukelisiwe, Mabasa Lawrence, Kotzé-Hörstmann Liske, Sangweni Nonhlakanipho, Ramharack Pritika, Sharma Jyoti, Pheiffer Carmen, Arowolo Afolake, Sadie-Van Gijsen Hanél
Biomedical Research and Innovation Platform (BRIP), South African Medical Research Council (SAMRC), Tygerberg, 7505, South Africa.
Centre for Cardio-metabolic Research in Africa (CARMA), Division of Medical Physiology, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa.
Sci Rep. 2025 Jun 4;15(1):19700. doi: 10.1038/s41598-025-02001-2.
Metabolic dysfunction-associated steatotic liver disease (MASLD), which affects a significant portion of the global population, is linked to high-fat diets (HFD) and characterized by abnormal lipid accumulation and activation of inflammatory pathways in hepatocytes. The precise mechanisms underlying MASLD, especially the involvement of inflammatory cytokines in its pathophysiology, remain unclear. This study evaluated the changes and interactions of steatotic liver and inflammatory markers in an animal model of MASLD by feeding male Wistar rats a high-fat diet (HFD) for 17 weeks. After this period, the serum lipid profiles were assessed, along with liver enzymes, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). The changes in liver morphology and triglyceride levels were determined by histology and a colorimetric assay, respectively. Steatotic liver and inflammatory markers were measured using a RTProfilerPCRArray and validated with quantitative real-time PCR (qRT-PCR). Histological evaluations indicated that HFD livers exhibited macrovesicular steatosis and lobular inflammation. The HFD-fed group had significantly higher hepatic triglyceride levels than the controls (383 ± 23 mg/dL vs. 100 ± 9 mg/dL) and elevated serum lipid levels (p < 0.0001), along with increased liver aminotransferase levels. Gene expression analysis showed decreased adiponectin signaling (AdipoR2, p < 0.001) and upregulated de novo lipogenesis (Srebf1, p < 0.05). Notably, pro-inflammatory cytokines (Cxcl10, Ccl2, Ilβ, p < 0.001; TNF-α, p < 0.01) were significantly elevated, correlating with reduced hepatic glucose transporter Glut2 expression (p < 0.05), as confirmed by STRING analysis. These findings demonstrate that HFD consumption alters key genes and pathways involved in adiponectin and insulin signalling, lipogenesis, and inflammatory responses, thereby contributing to the pathogenesis of MASLD. Additionally, it identifies a comprehensive chemokine expression profile, highlighting potential therapeutic targets for MASLD.
代谢功能障碍相关脂肪性肝病（MASLD）影响着全球相当一部分人口，与高脂饮食（HFD）有关，其特征是肝细胞内脂质异常蓄积和炎症信号通路激活。MASLD的具体机制，尤其是炎症细胞因子在其病理生理学中的作用，仍不清楚。本研究通过给雄性Wistar大鼠喂食高脂饮食17周，评估了MASLD动物模型中脂肪性肝脏和炎症标志物的变化及相互作用。在此期间后，评估了血清脂质谱以及包括天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）在内的肝酶。分别通过组织学和比色法测定肝脏形态和甘油三酯水平的变化。使用RTProfilerPCRArray测量脂肪性肝脏和炎症标志物，并用定量实时PCR（qRT-PCR）进行验证。组织学评估表明，高脂饮食组肝脏表现出大泡性脂肪变性和小叶炎症。高脂饮食喂养组的肝脏甘油三酯水平显著高于对照组（383±23mg/dL对100±9mg/dL），血清脂质水平升高（p<0.0001），同时肝转氨酶水平升高。基因表达分析显示脂联素信号传导降低（AdipoR2，p<0.001），从头脂肪生成上调（Srebf1，p<0.05）。值得注意的是，促炎细胞因子（Cxcl10、Ccl2、Ilβ，p<0.001；TNF-α，p<0.01）显著升高，与肝脏葡萄糖转运蛋白Glut2表达降低相关（p<0.05），STRING分析证实了这一点。这些发现表明，食用高脂饮食会改变脂联素和胰岛素信号传导、脂肪生成和炎症反应中涉及的关键基因和信号通路，从而导致MASLD的发病机制。此外，它还确定了一个全面的趋化因子表达谱，突出了MASLD的潜在治疗靶点。
