Hepatic miR-363 promotes nonalcoholic fatty liver disease by suppressing INSIG1

IF 4.8 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
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引用次数: 0

Abstract

Nonalcoholic fatty liver disease (NAFLD) constitutes one of major worldwide health problem which typically progressively results in nonalcoholic steatohepatitis (NASH) and eventually cirrhosis and liver cancer. Liver-specific deletion of INSIG1 promotes SREBP1 nuclear translocation to activate downstream lipogenic genes expression, leading to lipid accumulation. However, the underlying pathogenesis of NAFLD, and particularly involved in miRNA participation are still to be thoroughly explored. Here, we found that miR-363-3p was significantly overexpressed in high-fat, high-cholesterol (HFHC) diet mice liver tissue and fatty acid-induced steatosis cells. miR-363-3p directly targets INSIG1 to inhibit its expression, thereby facilitating the cleavage of SREBP and nuclear translocation to activate subsequent transcription of lipogenic genes in vitro and in vivo. In addition, we identified apigenin, a natural flavonoid compound, inhibited miR-363-3p expression to up-regulate INSIG1 and suppress nuclear translocation of SREBP1, thereby down-regulated lipogenic genes expression in steatosis cells and HFHC diet mice liver tissues. Taken together, our results demonstrated that miR-363-3p as a key regulator of hepatic lipid homeostasis targeted INSIG1, and apigenin alleviated NAFLD through the miR-363-3p/INSIG1/SREBP1 pathway. This indicates that reduction of miR-363-3p levels as a possible treatment of hepatic steatosis and provides a potential new therapeutic strategy for targeting miRNA to ameliorate NAFLD.

Abstract Image

肝脏 miR-363 通过抑制 INSIG1 促进非酒精性脂肪肝的发生。
非酒精性脂肪肝(NAFLD)是世界性的主要健康问题之一,通常会逐渐发展为非酒精性脂肪性肝炎(NASH),最终导致肝硬化和肝癌。肝脏特异性缺失 INSIG1 会促进 SREBP1 核转位,激活下游致脂基因的表达,导致脂质积累。然而,非酒精性脂肪肝的潜在发病机制,尤其是 miRNA 的参与仍有待深入探讨。miR-363-3p直接靶向INSIG1,抑制其表达,从而促进SREBP的裂解和核转运,激活体外和体内致脂基因的后续转录。此外,我们还发现天然类黄酮化合物芹菜素能抑制 miR-363-3p 的表达,从而上调 INSIG1 并抑制 SREBP1 的核转位,从而下调脂肪变性细胞和高密度脂蛋白胆固醇饮食小鼠肝组织中致脂基因的表达。综上所述,我们的研究结果表明,miR-363-3p 是肝脏脂质平衡的关键调控因子,它靶向 INSIG1,芹菜素通过 miR-363-3p/INSIG1/SREBP1 通路缓解非酒精性脂肪肝。这表明,降低 miR-363-3p 水平是治疗肝脂肪变性的一种可能方法,并为靶向 miRNA 改善非酒精性脂肪肝提供了一种潜在的新治疗策略。
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来源期刊
Journal of Nutritional Biochemistry
Journal of Nutritional Biochemistry 医学-生化与分子生物学
CiteScore
9.50
自引率
3.60%
发文量
237
审稿时长
68 days
期刊介绍: Devoted to advancements in nutritional sciences, The Journal of Nutritional Biochemistry presents experimental nutrition research as it relates to: biochemistry, molecular biology, toxicology, or physiology. Rigorous reviews by an international editorial board of distinguished scientists ensure publication of the most current and key research being conducted in nutrition at the cellular, animal and human level. In addition to its monthly features of critical reviews and research articles, The Journal of Nutritional Biochemistry also periodically publishes emerging issues, experimental methods, and other types of articles.
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