Arindkar Shailendra Kumar, Singh Surender, Kumar Jerald Mahesh, Nagarajan Perumal
BRIC NII - Experimental Animal Facility, National Institute of Immunology, New Delhi 100 067, India.
CSIR CCMB -Centre for Cellular and Molecular Biology, Hyderabad 500 007, India.
Gene. 2025 Aug 15;961:149550. doi: 10.1016/j.gene.2025.149550. Epub 2025 May 6.
Genes play an important role in regulating insulin signaling, adipokines, oxidative stress, lipid metabolism, and inflammation in susceptibility and progression of Metabolic dysfunction-associated steatotic liver disease (MASLD). Among various genes, the LepR gene influences insulin sensitivity and controls lipid metabolism, contributing to the development of MASLD. Our previous study reported that a novel congenic mouse (WSB.db) with a LepR mutation exhibited resistance to MASLD. To further evaluate this strain for resistance, we fed this new mouse strain with LepR mutation and B6.db mice, the mouse model of metabolic disease with a high-fat diet as a second hit for 12 weeks and evaluated the pathophysiology, serum biochemistry, Quantitative real-time polymerase chain reaction (qPCR) to determine the expression of specific genes involved in the development of fatty changes in the liver and hepatic transcriptome signatures in liver tissue. In contrast to db/db (B6.db) mice, which exhibited all the pathological hallmarks for MASLD, the LepR mutant congenic strain was still resistant to developing liver steatosis. Transcriptome analysis with KEGG PATHWAY: hsa04932 revealed significant upregulation of AMPKγ3 and MApk10 (JNK3) in WSB.db mice, suggesting that congenic mice with the LepR mutation are resistant to MASLD without the liver pathology to effect. These results propose that the LepR mutation has a different impact on liver pathology depending on genetic background, indicating upregulation of specific genes in the development of MASLD. This study will facilitate the identification of therapeutic targets against MASLD with LepR mutation.
基因在调节胰岛素信号传导、脂肪因子、氧化应激、脂质代谢以及炎症反应方面，对代谢功能障碍相关脂肪性肝病（MASLD）的易感性和进展起着重要作用。在众多基因中，LepR基因影响胰岛素敏感性并控制脂质代谢，促使MASLD的发生发展。我们之前的研究报道，一种携带LepR突变的新型同源基因小鼠（WSB.db）对MASLD具有抗性。为了进一步评估该品系的抗性，我们用高脂饮食作为二次打击因素，分别喂养这种携带LepR突变的新小鼠品系和B6.db小鼠（代谢疾病小鼠模型）12周，并评估其病理生理学、血清生化指标，通过定量实时聚合酶链反应（qPCR）来确定参与肝脏脂肪变性发展的特定基因的表达以及肝脏组织中的肝脏转录组特征。与表现出MASLD所有病理特征的db/db（B6.db）小鼠不同，LepR突变同源基因品系仍对肝脏脂肪变性的发生具有抗性。通过KEGG通路：hsa04932进行的转录组分析显示，WSB.db小鼠中AMPKγ3和MApk10（JNK3）显著上调，这表明携带LepR突变的同源基因小鼠对MASLD具有抗性且无肝脏病理影响。这些结果表明，LepR突变对肝脏病理的影响因遗传背景而异，这表明在MASLD的发展过程中特定基因上调。本研究将有助于确定针对携带LepR突变的MASLD的治疗靶点。
