α-酮戊二酸经PI3K/AKT改善砷诱导的子代肝脂质沉积OA
α-ketoglutarate ameliorated arsenic-induced hepatic lipid deposition in offspring via PI3K/AKT signaling pathway
目的 探讨α-酮戊二酸(α-KG)对孕期砷暴露导致子代肝脏脂质沉积中的保护作用及机制.方法 SPF级8周龄癌症研究所(ICR)小鼠,雌雄2∶1交配后得到孕鼠共32只,将孕鼠随机分为4组:对照组、砷组、α-KG组、砷+α-KG组.在妊娠第0～16天(GD0～GD16),砷组和砷+α-KG组每天饮水暴露亚砷酸钠(NaAsO2)15 mg/L,α-KG组和砷+α-KG组使用α-KG(2 g/kg)每天进行灌胃.在GD16收集胎鼠肝脏,并测量胎鼠体质量与顶臀长;转录组分析对照组和砷组基因表达差异;液相色谱-串联质谱法(LC-MS/MS)检测胎鼠肝脏总三酰甘油(TGs)水平及其亚型;油红O染色观察肝脏组织病理变化;实时定量聚合酶链式反应(qPCR)检测胎鼠磷酸肌醇3-激酶(PI3K)、蛋白激酶B(AKT)、脂质代谢相关基因的表达水平.结果 转录组学分析显示,孕期砷暴露后导致胎肝2 144个基因下调和1 675个基因上调;与对照组相比,砷组胎鼠体质量和顶臀长降低(PTuKey<0.05),肝脏TGs水平升高(PTuKey<0.05);油红O染色结果显示,脂滴明显增加(PTuKey<0.01);qPCR检测结果显示脂质合成相关基因表达显著上调(PTuKey<0.05),β-氧化以及脂质降解相关基因表达下降(PTuKey<0.05),PI3K、AKT转录水平降低(PTuKey<0.05).与砷组相比,砷+α-KG组胎鼠体质量和顶臀长增加(PTuKey<0.05);肝脏TGs水平降低(PTuKey<0.05);油红O染色结果显示,脂滴显著减少(PTuKey<0.01);脂质合成相关基因表达下调(PTuKey<0.05),β-氧化以及脂质降解相关基因表达上调(PTuKey<0.05),PI3K、AKT转录水平上升(PTuKey<0.05).结论 α-KG可有效缓解孕期砷暴露导致的子代肝脏脂质沉积,其作用机制可能是通过激活PI3K/AKT,恢复脂质代谢稳态实现的.
Objective To investigate the protective effect of α-ketoglutarate(α-KG)on hepatic lipid deposition in offspring caused by arsenic exposure during pregnancy.Methods 8-week-old institute of cancer research(ICR)mice were mated in a ratio of 2∶1 between females and males,and the detection of vaginal plugs confirmed preg-nant.A total of 32 pregnant mice were randomly divided into four groups:control group,arsenic group,α-KG group,arsenic+α-KG group.On gestational day 0-16(GD0-GD16),the arsenic and arsenic+α-KG groups were ex-posed to sodium arsenite(NaAsO2,15 mg/L)in drinking water everyday,and the α-KG and arsenic+α-KG groups were gavaged with α-KG(2 g/kg)everyday.On GD16,pregnant mice were euthanized to collect fetal liver,and fe-tal body weight and crown-rump length were measured.Gene expression differences between the control group and the arsenic group were analyzed by transcriptome.The total triglycerides(TGs)and subtypes in fetal liver were de-tected by liquid chromatography tandem mass spectrometry(LC-MS/MS).Oil red O staining was used to observe the histopathological changes in the liver.Quantitative polymerase chain reaction(qPCR)was used to detect the expression level of genes related to lipid synthesis,transport,and degradation,and phosphatidylinositol 3'-kinase/protein kinase B(PI3K/AKT)in the liver of fetus.Results Transcriptomics analysis showed that 2 144 genes were downregulated and 1 675 genes were upregulated in the arsenic exposed fetal liver;body weight and crown-rump length were reduced(PTuKey<0.05);the level of hepatic TGs was elevated in arsenic group(PTuKey<0.05);oil-red O staining showed a significant increase in lipid droplets in arsenic group(PTuKey<0.01);the expression of lipid synthesis-related genes were significantly upregulated(PTuKey<0.05);the expression of β-oxidation-related genes and lipid degradation-related genes were downregulated(PTuKey<0.05);the expression of PI3K,AKT decreased(PTuKey<0.05).Compared with the arsenic group,the body weight and crown-rump length of fetus increased in the arsenic+α-KG group(PTuKey<0.05);the level of hepatic TGs decreased in the arsenic+α-KG group(PTuKey<0.05);oil red O staining showed lipid droplets significantly decreased(PTuKey<0.01);the expression of lipid synthesis-related genes were downregulated(PTuKey<0.05),the expression of β-oxidation-related genes and lipid degradation-related genes were upregulated(PTuKey<0.05);the expression levels of PI3K and AKT increased(PTuKey<0.05).Conclusion α-KG alleviated hepatic lipid deposition in offspring exposed to arsenic during pregnancy through ac-tivating PI3K/AKT signaling pathway.
暴双蕊;吴红艳;孙影;詹童;杨倩;梁心茹;万志雁;陈文一;张程
安徽医科大学公共卫生学院卫生毒理学系,合肥 230032||环境毒理学安徽普通高校省级重点实验室,合肥 230032||出生人口健康教育部重点实验室,合肥 230032安徽医科大学公共卫生学院卫生毒理学系,合肥 230032||环境毒理学安徽普通高校省级重点实验室,合肥 230032||出生人口健康教育部重点实验室,合肥 230032安徽医科大学公共卫生学院卫生毒理学系,合肥 230032||环境毒理学安徽普通高校省级重点实验室,合肥 230032||出生人口健康教育部重点实验室,合肥 230032安徽医科大学公共卫生学院卫生毒理学系,合肥 230032||环境毒理学安徽普通高校省级重点实验室,合肥 230032||出生人口健康教育部重点实验室,合肥 230032安徽医科大学公共卫生学院卫生毒理学系,合肥 230032||环境毒理学安徽普通高校省级重点实验室,合肥 230032||出生人口健康教育部重点实验室,合肥 230032安徽医科大学公共卫生学院卫生毒理学系,合肥 230032||环境毒理学安徽普通高校省级重点实验室,合肥 230032||出生人口健康教育部重点实验室,合肥 230032安徽医科大学公共卫生学院卫生毒理学系,合肥 230032||环境毒理学安徽普通高校省级重点实验室,合肥 230032||出生人口健康教育部重点实验室,合肥 230032环境毒理学安徽普通高校省级重点实验室,合肥 230032||出生人口健康教育部重点实验室,合肥 230032安徽医科大学公共卫生学院卫生毒理学系,合肥 230032||环境毒理学安徽普通高校省级重点实验室,合肥 230032||出生人口健康教育部重点实验室,合肥 230032
医药卫生
α-酮戊二酸砷脂质代谢PI3K/AKT肝脏脂质沉积孕期暴露子代
α-ketoglutaratearseniclipid metabolismPI3K/AKTliver lipid depositiongestational exposureoffspring
《安徽医科大学学报》 2026 (2)
225-232,8
国家自然科学基金项目(编号:82173565)安徽省高校中青年教师培养行动项目(编号:DTR2023012)出生人口健康教育部重点实验室"本科生开放课题"项目(编号:JKBK20249) Fund programs National Natural Science Foundation of China(No.82173565)Project for Cultivation of Young and Middle-aged Teachers in Univerisities of Anhui Province(No.DTR2023012)Open Project(for Un-dergraduates)of Key Laboratory of Population Health Across Life Cycle(AHMU),MOE(No.JKBK20249)
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