Heterozygous GAA knockout is nonconsequential on metabolism and the spatial liver transcriptome in high-fat diet induced obese and prediabetic mice

The liver is composed of periportal and perivenous hepatocytes that have different metabolic profiles. This study used spatial transcritpomics to identify how high-fat diet induced obesity and heterozygous GAA knockout impacted the periportal and perivenous transcriptome. The spatial transcritpomics analysis revealed that heterozygous GAA knockout had no impact on liver transcriptomes. However, the high-fat diet, compared to the low-fat diet, reduced metabolic pathway gene abundance in both zones, while uniquely reducing ribosome gene abundance in perivenous hepatocytes. Four groups of mice were included in the analysis including 1) wildtype low-fat fed mice, 2) heterozygous GAA knockout low-fat diet fed mice, 3) wildtype high-fat diet fed mice, and 4) heterozygous GAA knockout hig-fat diet fed mice. Formalin fixed paraffin embedded liver sections were used for the spatial transcriptomics analysis.

肝脏由门周肝细胞与静脉周肝细胞构成，二者具有截然不同的代谢特征。本研究采用空间转录组学（spatial transcriptomics）技术，探究了高脂饮食诱导的肥胖与GAA基因杂合敲除对门周及静脉周肝细胞转录组的影响。空间转录组学分析结果显示，GAA基因杂合敲除对肝脏整体转录组未产生显著影响。然而相较于低脂饮食组，高脂饮食组在两个肝细胞区域中均下调了代谢通路基因的表达丰度，且仅在静脉周肝细胞中特异性降低了核糖体基因的表达丰度。本分析共纳入四组实验小鼠：1）野生型（wildtype）低脂饮食喂养小鼠；2）GAA基因杂合敲除低脂饮食喂养小鼠；3）野生型高脂饮食喂养小鼠；4）GAA基因杂合敲除高脂饮食喂养小鼠。本次空间转录组学分析采用福尔马林固定石蜡包埋的肝脏组织切片作为实验样本。