Inhibition of mmu_circ_0009303 improves metabolic dysfunction-associated steatotic liver disease by regulating lipid metabolism and oxidative stress.

IF 1.3 4区 医学 Q4 ENDOCRINOLOGY & METABOLISM
Ju Zhou, Wu Li, Xiaowei Chi, Dingchun Li, Chunxia Yang, Zhiwen Duan
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Abstract

Circular RNAs (circRNAs) play an important role in regulating inflammation and oxidative stress during the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the underlying mechanism is unclear. This study aimed to determine the role of mmu_circ_0009303 in MASLD. We used a bioinformatics approach to identify potential targets and established an in vitro model of MASLD. Oil red O staining, cell transfection and dual-luciferase reporter assay were used to determine the role of mmu_circ_0009303. The results indicated that the mmu_circ_0009303 expression was significantly increased in the MASLD model both in vitro and in vivo and was associated with oxidative stress levels and inflammation. Moreover, bioinformatics analyses revealed that miRNA-182-5p and Foxo3 are targets of mmu_circ_0009303 and miRNA-182-5p, respectively. In the in vitro MASLD model, mmu_circ_0009303 promoted fat deposition in NCTC1469 cells, which was induced by free fatty acid (FFA) through the regulation of miRNA-182-5p/Foxo3. The expression of miRNA-182-5p and Forkhead box O3 (Foxo3) was associated with mmu_circ_0009303 expression in the liver of mice with MASLD, which was induced by a high-fat diet. Furthermore, mmu_circ_0009303 may be involved in regulating the expression of lipid metabolism-related regulatory proteins, such as CPT1A, SLC27A4, ACBD3, SREBP1, FAS, PPARα, and PPARγ. Taken together, mmu_circ_0009303 promotes oxidative stress, inflammation, and excessive fat accumulation in NCTC1469 cells induced by FFA through the regulation of miRNA-182-5p/Foxo3 and lipid metabolism-related regulatory proteins. These findings provide a potential target for the treatment of MASLD.

通过调节脂质代谢和氧化应激,抑制 mmu_circ_0009303 可改善代谢功能障碍相关的脂肪性肝病。
环状 RNA(circRNA)在代谢功能障碍相关性脂肪性肝病(MASLD)的发病过程中对炎症和氧化应激起着重要的调节作用,但其潜在机制尚不清楚。本研究旨在确定 mmu_circ_0009303 在 MASLD 中的作用。我们利用生物信息学方法确定了潜在的靶点,并建立了 MASLD 的体外模型。通过油红 O 染色、细胞转染和双荧光素酶报告实验来确定 mmu_circ_0009303 的作用。结果表明,mmu_circ_0009303的表达在MASLD模型的体内外均显著增加,并与氧化应激水平和炎症相关。此外,生物信息学分析表明,miRNA-182-5p 和 Foxo3 分别是 mmu_circ_0009303 和 miRNA-182-5p 的靶标。在体外 MASLD 模型中,mmu_circ_0009303 通过调控 miRNA-182-5p/Foxo3 促进了游离脂肪酸(FFA)诱导的 NCTC1469 细胞的脂肪沉积。在高脂饮食诱导的MASLD小鼠肝脏中,miRNA-182-5p和叉头框O3(Foxo3)的表达与mmu_circ_0009303的表达有关。此外,mmu_circ_0009303 可能参与调节脂质代谢相关调节蛋白的表达,如 CPT1A、SLC27A4、ACBD3、SREBP1、FAS、PPARα 和 PPARγ。综上所述,mmu_circ_0009303 通过调控 miRNA-182-5p/Foxo3 和脂质代谢相关调控蛋白,促进氧化应激、炎症和脂肪酸诱导的 NCTC1469 细胞中脂肪的过度积累。这些发现为治疗 MASLD 提供了一个潜在靶点。
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来源期刊
Endocrine journal
Endocrine journal 医学-内分泌学与代谢
CiteScore
4.30
自引率
5.00%
发文量
224
审稿时长
1.5 months
期刊介绍: Endocrine Journal is an open access, peer-reviewed online journal with a long history. This journal publishes peer-reviewed research articles in multifaceted fields of basic, translational and clinical endocrinology. Endocrine Journal provides a chance to exchange your ideas, concepts and scientific observations in any area of recent endocrinology. Manuscripts may be submitted as Original Articles, Notes, Rapid Communications or Review Articles. We have a rapid reviewing and editorial decision system and pay a special attention to our quick, truly scientific and frequently-citable publication. Please go through the link for author guideline.
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