Institute of Metabolism and Regenerative Medicine, Digestive Endoscopic Center, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Physiology and Pathophysiology, Shanghai Key Laboratory of Bioactive Small Molecules, State Key Laboratory of Medical Neurobiology, School of Basic Medical Sciences, and Jinshan Hospital, Fudan University, Shanghai, China; Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Mol Metab. 2024 Nov;89:102030. doi: 10.1016/j.molmet.2024.102030. Epub 2024 Sep 16.
Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are characterized by excessive triglyceride accumulation in the liver. However, due to an incomplete understanding of its pathogenesis, more efforts are needed to identify specific and effective treatments. N4-acetylcytidine (ac4C) is a newly discovered RNA modification to regulate mRNA. N-acetyltransferase 10 (NAT10) has not been fully explored in MASLD and MASH.
The clinical relevance of NAT10 was evaluated based on its expression in various mouse and human models of MASLD and MASH. Acetylated RNA immunoprecipitation sequencing and mRNA stability assays were used to explore the role of NAT10 in regulating ac4C modification and expression of target genes. Genetically engineered mice were employed to investigate the role of NAT10 in MASLD and MASH progression.
Hepatic NAT10 expression was significantly increased in multiple mice and humans of MASLD and MASH. Genetic knockout of NAT10 protected mice from diet-induced hepatic steatosis and steatohepatitis, whereas overexpression of NAT10 exacerbated high-fat-diet-induced liver steatosis. Mechanistically, NAT10 binds to Srebp-1c mRNA, promoting its stability and expression, thereby upregulating lipogenic enzymes. Treatment with Remodelin, a NAT10-specific inhibitor, effectively ameliorates liver steatosis and dyslipidemia in a preclinical mouse model.
Our findings indicate that NAT10 could regulate lipid metabolism in MASLD and MASH by stabilizing Srebp-1c mRNA and upregulating lipogenic enzymes. This study highlights the role of NAT10 and RNA acetylation in the pathogenesis of MASLD and MASH. Thus, our findings suggest a promising new therapeutic approach, such as the use of NAT10 inhibitor, for treating metabolic liver disease.
代谢相关脂肪性肝病（MASLD）和代谢相关脂肪性肝炎（MASH）的特征是肝脏中甘油三酯过度积累。然而，由于对其发病机制的不完全了解，需要更多的努力来确定特定和有效的治疗方法。N4-乙酰胞苷（ac4C）是一种新发现的调节 mRNA 的 RNA 修饰物。N-乙酰转移酶 10（NAT10）在 MASLD 和 MASH 中的作用尚未得到充分探索。
根据其在各种 MASLD 和 MASH 小鼠和人类模型中的表达，评估了 NAT10 的临床相关性。采用乙酰化 RNA 免疫沉淀测序和 mRNA 稳定性测定来探索 NAT10 在调节 ac4C 修饰和靶基因表达中的作用。利用基因工程小鼠研究 NAT10 在 MASLD 和 MASH 进展中的作用。
多种 MASLD 和 MASH 的小鼠和人类肝脏中 NAT10 的表达明显增加。NAT10 的基因敲除可保护小鼠免受饮食诱导的肝脂肪变性和脂肪性肝炎，而过表达 NAT10 则加剧高脂肪饮食诱导的肝脂肪变性。机制上，NAT10 与 Srebp-1c mRNA 结合，促进其稳定性和表达，从而上调脂肪生成酶。NAT10 特异性抑制剂 Remodelin 在临床前小鼠模型中可有效改善肝脂肪变性和血脂异常。
我们的研究结果表明，NAT10 通过稳定 Srebp-1c mRNA 和上调脂肪生成酶来调节 MASLD 和 MASH 中的脂质代谢。本研究强调了 NAT10 和 RNA 乙酰化在 MASLD 和 MASH 发病机制中的作用。因此，我们的研究结果表明，使用 NAT10 抑制剂等有前途的新治疗方法可能用于治疗代谢性肝病。
