司美格鲁肽在蛋氨酸胆碱缺乏饮食诱导的非酒精性脂肪性肝病大鼠肝脏脂质代谢中的研究
Effect of Semaglutide in Hepatic Lipid Metabolism of Rats in a Methionine-choline Deficient Diet-induced Non-Alcoholic Fatty Liver Disease Model
背景??司美格鲁肽作为胰高血糖素样肽1受体激动剂之一，对于缓解非酒精性脂肪性肝病（NAFLD）的进展有很大的潜力但是作用机制尚未明确。目的 ?研究司美格鲁肽对肝脏脂质代谢的影响，进一步探究非酒精性脂肪性肝病的发病机制及帮助临床做出诊断和治疗。方法 ?2022年9—11月30只SPF级5~8周龄雄性SD大鼠，体质量（180±20）g，大鼠适应性喂养1周后随机分为空白组、模型组和干预组，每组10只。制备NAFLD大鼠模型，干预组大鼠给予司美格鲁肽40μg/kg，溶解于0.9%氯化钠溶液皮下注射，空白组和模型组大鼠皮下注射等量0.9%氯化钠溶液。观察大鼠一般情况，苏木素-伊红（HE）染色和油红O染色观察大鼠肝组织病变情况，检测大鼠血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）水平，检测大鼠肝组织三酰甘油（TG）水平。反转录聚合酶链反应（RT-PCR）检测脂肪酸合成酶（FAS）、乙酰辅酶A羧化酶（ACC1）、肉毒碱棕榈酰转移酶1α（CPT1α）、乙酰辅酶A氧化酶（AOX）、脂肪酸转运蛋白36（FAT/CD36）、肝脏脂肪酸结合蛋白（LFABP）、载脂蛋白B（ApoB）、微粒体甘油三酯转移蛋白（MTTP）mRNA表达量。蛋白质印迹试验（Westernblot）检测FAT/CD36蛋白含量。结果 ?实验期间各组动物均无死亡，空白组大鼠毛发柔顺、有光泽、精神状态良好，模型组和干预组大鼠随喂养时间增长，表现为体质量明显减轻，毛发紊乱、无光泽，活动减弱，精神萎靡。干预结束后模型组体质量低于空白组，干预组高于模型组（P<0.05）。模型组肝脏质量高于空白组，干预组低于模型组（P<0.05）。模型组ALT、AST、TG水平高于空白组，干预组ALT、AST、TG水平低于模型组（P<0.05）。模型组CPT1α、AOX、LFABP、ApoB、MTTP低于空白组，干预组FAT/CD36低于模型组（P<0.05）。模型组FAT/CD36高于空白组，干预组低于模型组（P<0.05）。结论 ?司美格鲁肽缓解了NAFLD大鼠肝脏的脂质沉积，这可能与FAT/CD36蛋白表达下调有关。
Background?Semaglutideas one of the glucagon-like peptide-1GLP-1receptor agonistshas significant potential for alleviating the progression of non-alcoholic fatty liver diseaseNAFLD. Howeverits mechanism of action remains unclear. Objective?To investigate the effect of semaglutide on hepatic lipid metabolismfurther explore the pathogenesis of NAFLD and help clinical diagnosis and treatment. Methods?Between September and November 202230 SPF grade male SD ratsaged 5-8 weeks with a body weight of18020gwere acclimatized for one week and then randomly divided into three groups of controlmodeland interventionwith 10 rats in each. The NAFLD rat model was preparedand the intervention group received semaglutide at 40 g/kg dissolved in 0.9% saline solution subcutaneously. The control and model groups received an equivalent volume of 0.9% saline subcutaneously. The general condition of the rats was observedwith hematoxylin-eosinHEstaining and Oil Red O staining to examine liver tissue lesions. Serum levels of alanine aminotransferase ALTaspartate aminotransferaseASTand liver tissue triglycerideTGlevels were measured. Real-time polymerase chain reactionRT-PCRwas used to detect mRNA expression of fatty acid synthaseFASacetyl-CoA carboxylase 1ACC1 carnitine palmitoyltransferase 1CPT1acyl-CoA oxidaseAOXfatty acid transport protein 36FAT/CD36liver fatty acid-binding proteinLFABPapolipoprotein BApoBand microsomal triglyceride transfer proteinMTTP.Western blot assay was used to detect FAT/CD36 protein levels. Results?There was no death of animals in all groups during the experimental periodand the rats in the control group exhibited smooth and glossy fur with good spiritwhile the rats in the model group and intervention group showed a significant reduction in body weightdisorganized and lusterless hairreduced activity and depressed spirit with the increase in feeding time. The body weight of the model group was lower than that of the control group at the end of the interventionand the intervention group was higher than that of the model groupP<0.05). The liver weight of the model group was higher than the control groupand lower in the intervention groupP<0.05. The levels of ALTASTand TG were higher than those in the model group than in the control groupand lower in the intervention groupP<0.05. The levels of CPT1AOXLFABPApoBand MTTP were lower in the model group than in the control groupand the level of FAT/CD36 was lower in the intervention groupP<0.05. The model group had higher levels of FAT/CD36 than the control groupand the intervention group had lower levels than the model groupP<0.05. Conclusion?Semaglutide alleviated hepatic lipid deposition in NAFLD ratspotentially related to the downregulation of FAT/CD36 protein expression.
郭永泽、董慧聪、李沙、张全爱、王恺悌、卢晓飞
基础医学药学
非酒精性脂肪性肝病司美格鲁肽脂质代谢脂肪酸转运蛋白 36
郭永泽,董慧聪,李沙,张全爱,王恺悌,卢晓飞.司美格鲁肽在蛋氨酸胆碱缺乏饮食诱导的非酒精性脂肪性肝病大鼠肝脏脂质代谢中的研究[EB/OL].(2024-11-26)[2025-08-02].https://chinaxiv.org/abs/202411.00275.点此复制
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