肝星状细胞
肝损伤
酒精性肝病
下调和上调
胶质1
药理学
癌症研究
纤维化
细胞外基质
肝病
化学
刺猬信号通路
细胞生物学
医学
信号转导
内分泌学
内科学
肝硬化
生物
生物化学
基因
作者
Virender Kumar,Bharti Sethi,Dalton W. Staller,Xiaoqing Xin,Jingyi Ma,Yuxiang Dong,Geoffrey A. Talmon,Ram I. Mahato
出处
期刊:Biomaterials
[Elsevier]
日期:2023-04-01
卷期号:295: 122049-122049
被引量:3
标识
DOI:10.1016/j.biomaterials.2023.122049
摘要
Alcohol-associated liver disease (ALD) and its complications are significant health problems worldwide. Several pathways in ALD are influenced by alcohol that drives inflammation, fatty acid metabolism, and fibrosis. Although miR-96 has become a key regulator in several liver diseases, its function in ALD remains unclear. In contrast, sonic hedgehog (SHH) signaling has a well-defined role in liver disease through influencing the activation of hepatic stellate cells (HSCs) and the inducement of liver fibrosis. In this study, we investigated the expression patterns of miR-96 and Hh molecules in mouse and human liver samples. We showed that miR-96 and Shh were upregulated in ethanol-fed mice. Furthermore, alcoholic hepatitis (AH) patient specimens also showed upregulated FOXO3a, TGF-β1, SHH, and GLI2 proteins. We then examined the effects of Hh inhibitor MDB5 and anti-miR-96 on inflammatory and extracellular matrix (ECM)-related genes. We identified FOXO3 and SMAD7 as direct target genes of miR-96. Inhibition of miR-96 decreased the expression of these genes in vitro in AML12 cells, HSC-T6 cells, and in vivo in ALD mice. Furthermore, MDB5 decreased HSCs activation and the expression of ECM-related genes, such as Gli1, Tgf-β1, and collagen. Lipid nanoparticles (LNPs) loaded with the combination of MDB5, and anti-miR-96 ameliorated ALD in mice. Our study demonstrated that this combination therapy could serve as a new therapeutic target for ALD.
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