Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, China.
Cell Mol Life Sci. 2024 Sep 11;81(1):398. doi: 10.1007/s00018-024-05434-6.
Abnormal lipid deposition is an important driver of the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). MicroRNA-411-5p (miR-411-5p) and eukaryotic translation initiation factor 4γ2 (EIF4G2) are related to abnormal lipid deposition, but the specific mechanism is unknown.
A high-fat, high-cholesterol diet (HFHCD) and a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) and a high-fructose diet (HFrD) were used to establish MASLD rat and mouse models, respectively. MiR-411-5p agomir and mimic were used to upregulate the miR-411-5p in vivo and in vitro, respectively. Adeno-associated virus type 8 (AAV8) carrying EIF4G2 short hairpin RNA (shRNA) and small interfering RNA (siRNA) were used to downregulate the EIF4G2 expression in vivo and in vitro, respectively. Liver histopathological analysis, Biochemical analysis and other experiments were used to explore the functions of miR-411-5p and EIF4G2.
MiR-411-5p was decreased in both MASLD rats and mice, and was negatively correlated with liver triglycerides and serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. Upregulation of miR-411-5p alleviated liver lipid deposition and hepatocellular steatosis. Moreover, miR-411-5p targeted and downregulated EIF4G2. Downregulation of EIF4G2 not only reduced liver triglycerides and serum ALT and AST levels in MASLD model, but also alleviated lipid deposition. Notably, upregulation of miR-411-5p and downregulation of EIF4G2 led to the reduction of forkhead box class O3 (FOXO3) and inhibited the expression of sterol regulatory-element binding protein 1 (SREBP1), acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), thereby reducing fatty acid synthesis.
Upregulation of miR-411-5p inhibits EIF4G2 to reduce the FOXO3 expression, thereby reducing fatty acid synthesis and alleviating abnormal lipid deposition in MASLD.
异常脂质沉积是代谢功能障碍相关脂肪性肝病（MASLD）进展的重要驱动因素。微小 RNA-411-5p（miR-411-5p）和真核翻译起始因子 4γ2（EIF4G2）与异常脂质沉积有关，但具体机制尚不清楚。
采用高脂肪、高胆固醇饮食（HFHCD）和胆碱缺乏、L-氨基酸定义的高脂肪饮食（CDAHFD）和高果糖饮食（HFrD）分别建立 MASLD 大鼠和小鼠模型。miR-411-5p 激动剂和模拟物分别用于体内和体外上调 miR-411-5p。携带 EIF4G2 短发夹 RNA（shRNA）和小干扰 RNA（siRNA）的腺相关病毒 8（AAV8）分别用于体内和体外下调 EIF4G2 的表达。采用肝组织病理分析、生化分析等实验方法探讨 miR-411-5p 和 EIF4G2 的功能。
在 MASLD 大鼠和小鼠中，miR-411-5p 表达均降低，与肝甘油三酯和血清丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）水平呈负相关。上调 miR-411-5p 可减轻肝脏脂质沉积和肝细胞脂肪变性。此外，miR-411-5p 靶向并下调 EIF4G2。下调 EIF4G2 不仅降低 MASLD 模型肝甘油三酯和血清 ALT、AST 水平，还减轻脂质沉积。值得注意的是，上调 miR-411-5p 和下调 EIF4G2 可降低叉头框 O3（FOXO3）并抑制固醇调节元件结合蛋白 1（SREBP1）、乙酰辅酶 A 羧化酶 1（ACC1）和脂肪酸合酶（FASN）的表达，从而减少脂肪酸合成。
上调 miR-411-5p 抑制 EIF4G2 减少 FOXO3 的表达，从而减少 MASLD 中脂肪酸的合成并减轻异常脂质沉积。
