Lin28 promoting the protective effect of PMSCs on hepatic ischaemia–reperfusion injury by regulating glucose metabolism

Zhou, Xi; Li, Junbo; Wang, Jin; Yang, Huifang; Xie, Xiaoyun; Chen, Zhishui; Zhang, Bo

doi:10.1111/jcmm.17739

J Cellular Molecular Medi

2023

DOI: 10.1111/jcmm.17739

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Lin28 promoting the protective effect of PMSCs on hepatic ischaemia–reperfusion injury by regulating glucose metabolism

Xi Zhou

Junbo Li

Jin Wang

et al.

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

Pan,

Yu,

Song

et al. 2024

The FASEB Journal

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Liver transplantation (LT) is the only effective method to treat end‐stage liver disease. Hepatic ischemia‐reperfusion injury (IRI) continues to limit the prognosis of patients receiving LT. Histone deacetylase 6 (HDAC6) is a unique HDAC member involved in inflammation and apoptosis. However, its role and mechanism in hepatic IRI have not yet been reported. We examined HDAC6 levels in liver tissue from LT patients, mice challenged with liver IRI, and hepatocytes subjected to hypoxia/reoxygenation (H/R). In addition, HDAC6 global‐knockout (HDAC6‐KO) mice, adeno‐associated virus‐mediated liver‐specific HDAC6 overexpressing (HDAC6‐LTG) mice, and their corresponding controls were used to construct hepatic IRI models. Hepatic histology, inflammatory responses, and apoptosis were detected to assess liver injury. The molecular mechanisms of HDAC6 in hepatic IRI were explored in vivo and in vitro. Moreover, the HDAC6‐selective inhibitor tubastatin A was used to detect the therapeutic effect of HDAC6 on liver IRI. Together, our results showed that HDAC6 expression was significantly upregulated in liver tissue from LT patients, mice subjected to hepatic I/R surgery, and hepatocytes challenged by hypoxia/reoxygenation (H/R) treatment. Compared with control mice, HDAC6 deficiency mitigated liver IRI by inhibiting inflammatory responses and apoptosis, whereas HDAC6‐LTG mice displayed the opposite phenotype. Further molecular experiments show that HDAC6 bound to and deacetylated AKT and HDAC6 deficiency improved liver IRI by activating PI3K/AKT/mTOR signaling. In conclusion, HDAC6 is a key mediator of hepatic IRI that functions to promote inflammation and apoptosis via PI3K/AKT/mTOR signaling. Targeting hepatic HDAC6 inhibition may be a promising approach to attenuate liver IRI.

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Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

Pan,

Yu,

Song

et al. 2024

The FASEB Journal

View full text Add to dashboard Cite

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Lin28 promoting the protective effect of PMSCs on hepatic ischaemia–reperfusion injury by regulating glucose metabolism

Zhou

Wang

et al. 2023

J Cellular Molecular Medi

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Maresin1 alleviates liver ischemia/reperfusion injury by reducing liver macrophage pyroptosis

Zeng

Xian

et al. 2023

J Transl Med

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Background Cell pyroptosis has a strong proinflammatory effect, but it is unclear whether pyroptosis of liver macrophages exacerbates liver tissue damage during liver ischemia‒reperfusion (I/R) injury. Maresin1 (MaR1) has a strong anti-inflammatory effect, and whether it can suppress liver macrophage pyroptosis needs further study. Methods This study aimed to investigate whether MaR1 can alleviate liver I/R injury by inhibiting macrophage pyroptosis. The effects of MaR1 on cell pyroptosis and mitochondrial damage were studied by dividing cells into control, hypoxia/reoxygenation, and hypoxia/reoxygenation + MaR1 groups. Knocking out RORa was used to study the mechanism by which MaR1 exert its protective effects. Transcriptome analysis, qRT‒PCR and Western blotting were used to analyze gene expression. Untargeted metabolomics techniques were used to analyze metabolite profiles in mice. Flow cytometry was used to assess cell death and mitochondrial damage. Results We first found that MaR1 significantly reduced liver I/R injury. We observed that MaR1 decreased liver I/R injury by inhibiting liver macrophage pyroptosis. Then, we discovered that MaR1 promotes mitochondrial oxidative phosphorylation, increases the synthesis of ATP, reduces the generation of ROS, decreases the impairment of mitochondrial membrane potential and inhibits the opening of mitochondrial membrane permeability transition pores. MaR1 inhibits liver macrophage pyroptosis by protecting mitochondria. Finally, we found that MaR1 exerts mitochondrial protective effects through activation of its nuclear receptor RORa and the PI3K/AKT signaling pathway. Conclusions During liver I/R injury, MaR1 can reduce liver macrophage pyroptosis by reducing mitochondrial damage, thereby reducing liver damage.

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Lin28 promoting the protective effect of PMSCs on hepatic ischaemia–reperfusion injury by regulating glucose metabolism

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 3 publications

References 56 publications

Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

Histone deacetylase 6 deficiency protects the liver against ischemia/reperfusion injury by activating PI3K/AKT/mTOR signaling

Lin28 promoting the protective effect of PMSCs on hepatic ischaemia–reperfusion injury by regulating glucose metabolism

Maresin1 alleviates liver ischemia/reperfusion injury by reducing liver macrophage pyroptosis

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