Fenofibrate inhibits MOXD1 and PDZK1IP1 expression and improves lipid deposition and inflammation in mice with alcoholic fatty liver

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  • 作者:Tongtong Pan, Zhiguang Zhao, Jianshuang Lu, Hong Wen, Jiarong Zhang, Yali Xu, Yongping Chen, Xiaoya Jin
  • 期刊:LIFE SCIENCES
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Aims Alcoholic liver disease (ALD) can develop into cirrhosis and hepatocellular carcinoma but no specific drugs are available. Fenofibrate is therapeutically effective in ALD, however, the exact mechanism remains unknown. We explored the hub genes of ALD and the role of fenofibrate in ALD. Main methods The hub genes of ALD were screened by bioinformatics method, and their functional enrichment, signalling pathways , target genes and their correlation with immune microenvironment and pathogenic genes were analysed. We also analysed the binding affinity of fenofibrate to proteins of hub genes using molecular docking techniques, and the effects on hub gene expression, lipid deposition , oxidative stress and inflammation in the liver of National Institute on Alcohol Abuse and Alcoholism (NIAAA) model mice. The regulatory effects of fenofibrate on MOXD1 and PDZK1P1 were investigated after gene silencing of peroxisome proliferator-activated receptor-α ( Ppar-α) . Key findings Hub genes identified, including monooxygenase DBH-like 1 ( MOXD1 ), PDZK1-interacting protein 1 ( PDZK1IP1 ) and solute carrier 51 β ( SLC51B ), are highly predictive for ALD. Hepatic MOXD1 and PDZK1IP1 expression was elevated in patients with ALD and NIAAA model mice, with no significant difference in SLC51B expression between the groups. Fenofibrate binds tightly to MOXD1 and PDZK1IP1, inhibits their hepatic expression independently of PPAR-α signalling, and ameliorates lipid deposition, oxidative stress and inflammatory responses in NIAAA model mice. Significance MOXD1 and PDZK1IP1 are key genes in ALD progression; fenofibrate improves liver damage in NIAAA model mice by downregulating their expression. Our findings provide insight for improving diagnostic and therapeutic strategies for ALD.

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