Chu Xiaolong, Hou Yanting, Peng Chaoling, Li Wei, Liang Maodi, Mei Jin, Qian Meiyu, Wang Juan, Xu Shibo, Jiang Yidan, Wen Xin, Chen Yao, Yuan Fangyuan, Xie Jianxin, Wang Cuizhe, Zhang Jun
Department of Basic Medicine, Medical College, Shihezi University, Shihezi, Xinjiang, China; Department of Medical Genetics, Medical College of Tarim University, Alar, Xinjiang, China.
Department of Basic Medicine, Medical College, Shihezi University, Shihezi, Xinjiang, China; Laboratory of Xinjiang Endemic and Ethic Diseases, Shihezi University, Shihezi, Xinjiang, China.
J Lipid Res. 2025 May 6;66(6):100818. doi: 10.1016/j.jlr.2025.100818.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide. This study investigates the role of serum miR-548ag in regulating lipid metabolism and its contribution to MASLD in obesity. We found that miR-548ag levels were significantly elevated in the serum of both obese and MASLD patients and positively correlated with body mass index, fasting plasma glucose, triglycerides, total cholesterol, LDL, HDL, aspartate aminotransferase, and alanine aminotransferase levels. Additionally, miR-548ag expression was significantly higher in the liver and abdominal adipose tissue of obese individuals than those of normal weight. In vitro studies in HepG2 and L02 cells, along with previous findings, demonstrated that miR-548ag promotes fatty acid synthase (FASN) expression by inhibiting DNA methyltransferase 3B (DNMT3B), thereby enhancing lipid synthesis. This was confirmed in two mouse models: one with tail vein injections of miR-548ag mimic/inhibitor adeno-associated viruses and another with tail vein injections of exosomes from serum of normal-weight and obese individuals. Both models showed that miR-548ag upregulated FASN through DNMT3B inhibition, leading to increased lipid synthesis and larger hepatic lipid droplets, effects that were reversed by miR-548ag inhibition. Together, this study revealed a significant increase in the levels of exosome miR-548ag in the serum of obese patients, which reaches the liver through blood circulation. In the liver, miR-548ag can target and inhibit DNMT3B, upregulate FASN expression, and increase hepatic lipid synthesis, thereby promoting the development of MASLD.
代谢功能障碍相关脂肪性肝病（MASLD）是全球慢性肝病的主要原因。本研究调查了血清miR-548ag在调节脂质代谢中的作用及其对肥胖患者MASLD的影响。我们发现，肥胖和MASLD患者血清中miR-548ag水平显著升高，且与体重指数、空腹血糖、甘油三酯、总胆固醇、低密度脂蛋白、高密度脂蛋白、天冬氨酸转氨酶和丙氨酸转氨酶水平呈正相关。此外，肥胖个体肝脏和腹部脂肪组织中miR-548ag表达显著高于正常体重个体。在HepG2和L02细胞中的体外研究以及先前的研究结果表明，miR-548ag通过抑制DNA甲基转移酶3B（DNMT3B）促进脂肪酸合酶（FASN）表达，从而增强脂质合成。这在两种小鼠模型中得到证实：一种是尾静脉注射miR-548ag模拟物/抑制剂腺相关病毒，另一种是尾静脉注射正常体重和肥胖个体血清中的外泌体。两种模型均显示，miR-548ag通过抑制DNMT3B上调FASN，导致脂质合成增加和肝脂质滴增大，而miR-548ag抑制可逆转这些作用。总之，本研究揭示肥胖患者血清中外泌体miR-548ag水平显著升高，其通过血液循环到达肝脏。在肝脏中，miR-548ag可靶向并抑制DNMT3B，上调FASN表达，增加肝脏脂质合成，从而促进MASLD的发展。
