Inflammation and oxidative stress are key steps in the progression of non‑alcoholic steatohepatitis (NASH). Intervention in these two processes will therefore benefit NASH treatment. Peroxisome proliferator‑activated receptor γ (PPARγ), as a multiple functional transcription factor, has been reported to be involved in the prevention of NASH progression. However, the mechanism by which PPARγ prevents NASH remains to be elucidated. The present study demonstrated that the level of PPARγ was inversely correlated with that of microRNA (miRNA/miRs)‑21‑5p in both mice and humans with NASH. Activation of PPARγ inhibited lipid droplet accumulation, hepatic inflammation and oxidative stress by downregulating miR‑21‑5p in an in vitro model. Luciferase reporter and chromatin immunoprecipitation assays demonstrated that PPARγ suppressed transcriptional activity of miR‑21‑5p and bound to miR‑21‑5p promoter region. Furthermore, PPARγ downregulated miR‑21‑5p while miR‑21‑5p upregulated secreted frizzled‑related protein 5 (SFRP5) by targeting the 3'‑UTR of its mRNA. In vivo experiments revealed that PPARγ repressed inflammation and oxidative stress and miR‑21‑5p expression while increased SFRP5 level in a NASH mouse model. In summary, PPARγ attenuates inflammation and oxidative stress in NASH by modulating the miR‑21‑5p/SFRP5 pathway, thus holding promise of a new target for NASH treatment.

中文翻译：

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PPARγ通过调节miR-21-5p/SFRP5通路减轻非酒精性脂肪性肝炎的肝脏炎症和氧化应激。

炎症和氧化应激是非酒精性脂肪性肝炎 (NASH) 进展的关键步骤。因此，对这两个过程的干预将有利于 NASH 治疗。据报道，过氧化物酶体增殖物激活受体 γ (PPARγ) 作为一种多功能转录因子参与了 NASH 进展的预防。然而，PPARγ 预防 NASH 的机制仍有待阐明。本研究表明，在患有 NASH 的小鼠和人类中，PPARγ 的水平与 microRNA (miRNA/miRs)‑21‑5p 的水平呈负相关。PPARγ的激活通过在体外下调miR-21-5p来抑制脂滴积累、肝脏炎症和氧化应激模型。荧光素酶报告基因和染色质免疫沉淀测定表明，PPARγ 抑制了 miR-21-5p 的转录活性并与 miR-21-5p 启动子区域结合。此外，PPARγ 下调 miR-21-5p，而 miR-21-5p 通过靶向其 mRNA 的 3'-UTR 上调分泌的卷曲相关蛋白 5 (SFRP5)。体内实验表明，在 NASH 小鼠模型中，PPARγ 抑制炎症和氧化应激以及 miR-21-5p 表达，同时增加 SFRP5 水平。总之，PPARγ 通过调节 miR-21-5p/SFRP5 通路减轻 NASH 中的炎症和氧化应激，从而有望成为 NASH 治疗的新靶点。