目的:代谢功能障碍相关的脂肪变性肝病(MASLD)正在成为儿科人群中不断升级的健康问题。本研究旨在探讨N-乙酰转移酶10(NAT10)在母亲高脂饮食(HFD)诱导的子代早期MASLD中的作用。
方法:我们产生了雄性肝细胞特异性NAT10敲除(Nat10HKO)小鼠,并在食物或HFD喂养下将其与雌性Nat10fl/fl小鼠交配。体重,肝脏组织病理学,和脂质代谢相关基因的表达(Srebp1c,Fasn,Pparα,Cd36,Fatp2,Mttp,和Apob)在断奶时对雄性后代进行了评估。在体内和体外进行脂质摄取测定。进行mRNA稳定性评估和RNA免疫沉淀以确定NAT10调节的靶基因。
结果:雄性子代肝细胞NAT10缺失减轻了母体HFD诱导的围产期脂质积累,降低Srebp1c的表达水平,Fasn,Cd36,Fatp2,Mttp,和Apob,同时增强Pparα表达。此外,Nat10HKO雄性小鼠表现出降低的脂质摄取。体外,NAT10通过增强CD36和FATP2的mRNA稳定性来促进脂质摄取。RNA免疫沉淀分析显示NAT10和CD36/FATP2mRNA之间的直接相互作用。
结论:子代肝细胞中NAT10缺失通过降低CD36和FATP2的mRNA稳定性改善母体HFD诱导的肝脏脂肪变性,突出NAT10作为小儿MASLD的潜在治疗靶点。
OBJECTIVE: Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming an escalating health problem in pediatric populations. This study aimed to investigate the role of N-acetyltransferase 10 (NAT10) in maternal high-fat diet (HFD)-induced MASLD in offspring at early life.
METHODS: We generated male hepatocyte-specific NAT10 knockout (Nat10HKO) mice and mated them with female Nat10fl/fl mice under chow or HFD feeding. Body weight, liver histopathology, and expression of lipid metabolism-associated genes (Srebp1c, Fasn, Pparα, Cd36, Fatp2, Mttp, and Apob) were assessed in male offspring at weaning. Lipid uptake assays were performed both in vivo and in vitro. The mRNA stability assessment and RNA immunoprecipitation were performed to determine NAT10-regulated target genes.
RESULTS: NAT10 deletion in hepatocytes of male offspring alleviated perinatal lipid accumulation induced by maternal HFD, decreasing expression levels of Srebp1c, Fasn, Cd36, Fatp2, Mttp, and Apob while enhancing Pparα expression. Furthermore, Nat10HKO male mice exhibited reduced lipid uptake. In vitro, NAT10 promoted lipid uptake by enhancing the mRNA stability of CD36 and FATP2. RNA immunoprecipitation assays exhibited direct interactions between NAT10 and CD36/FATP2 mRNA.
CONCLUSIONS: NAT10 deletion in offspring hepatocytes ameliorates maternal HFD-induced hepatic steatosis through decreasing mRNA stability of CD36 and FATP2, highlighting NAT10 as a potential therapeutic target for pediatric MASLD.