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Molecular pathological characteristics and mechanisms of the liver in metabolic disease-susceptible transgenic pigs

文献类型： 外文期刊

作者： Du, Juan 1 ; Zhang, Kaiyi 1 ; Miao, Jiakun 1 ; Yang, Yu 1 ; Tian, Yuying 1 ; Wu, Tianwen 1 ; Tao, Cong 1 ; Wang, Yanfang 1 ; Yang, Shulin 1 ;

作者机构： 1.Chinese Acad Agr Sci CAAS, Inst Anim Sci, State Key Lab Anim Biotech Breeding, Beijing 100193, Peoples R China

关键词： Transgenic pigs; ETNPPL; GABBR2; BMP8B; Bis (monoacylglycerol) phosphates; Sulfatides

期刊名称：LIFE SCIENCES （ 影响因子：5.1； 五年影响因子：5.4 ）

ISSN： 0024-3205

年卷期： 2025 年 362 卷

页码：

收录情况： SCI

摘要： Aims: This study aimed to explore the molecular pathological mechanisms of the liver in metabolic disease- susceptible transgenic pigs via multiomics analysis. Materials and methods: The triple-transgenic ( PNPLA3 I148M-GIPR dn-hIAPP ) pig model (TG pig) was successfully constructed in our laboratory via the CRISPR/Cas9 technique previously described. Wild-type (WT) pigs and TG pigs after 2 or 12 months of high-fat and high-sucrose diet (HFHSD) induction (WT2, TG2, WT12, and TG12 groups, respectively) were used as materials. The transcriptome, metabolome, and lipidome were used to investigate the molecular mechanisms of the liver in pigs. Key findings: The TG2 pigs presented mild metaflammation and insulin resistance (IR) which was similar to WT12 pigs. Compared with the other three groups, the TG12 pigs presented severe hepatocyte ballooning, fat deposition, and portal area fibrosis. The transcriptome data suggested that the TG2 pigs presented upregulated gene expression in the extracellular matrix (ECM). The TG12 pigs presented more severe metaflammation and exhibited imbalanced glycolipid metabolism. Interestingly, genes such as ETNPPL, GABBR2, and BMP8B might be key regulatory targets for liver injury. The metabolome and lipidome suggested that long-chain polyunsaturated fatty acids (LCPUFAs) and phospholipids with corresponding LCPUFAs were remodelled. Importantly, bis(monoacylglycerol) phosphates (BMPs) and sulfatides (SLs) could be the key regulatory metabolites in liver injury. Significance: ETNPPL, GABBR2, and BMP8B might be potential therapeutic targets for liver injury. BMPs and SLs might be biomarkers for the diagnosis and treatment of liver diseases.

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