Phosphatidic acid-enabled MKL1 contributes to liver regeneration:Translational implication in liver failure

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外文摘要：Liver regeneration following injury aids the restoration of liver mass and the recovery of liver function.In the present study we investigated the contribution of megakaryocytic leukemia 1(MKL1),a transcriptional modulator,to liver regeneration.We report that both MKL1 expression and its nuclear translocation correlated with hepatocyte proliferation in cell and animal models of liver regeneration and in liver failure patients.Mice with MKL1 deletion exhibited defective regenerative response in the liver.Transcriptomic analysis revealed that MKL1 interacted with E2F1 to program pro-regenerative tran-scription.MAPKAPK2 mediated phosphorylation primed MKL1 for its interaction with E2F1.Of inter-est,phospholipase d2 promoted MKL1 nuclear accumulation and liver regeneration by catalyzing production of phosphatidic acid(PA).PA administration stimulated hepatocyte proliferation and enhanced survival in a MKL1-dependent manner in a pre-clinical model of liver failure.Finally,PA levels was detected to be positively correlated with expression of pro-regenerative genes and inversely corre-lated with liver injury in liver failure patients.In conclusion,our data reveal a novel mechanism whereby MKL1 contributes to liver regeneration.Screening for small-molecule compounds boosting MKL1 activ-ity may be considered as a reasonable approach to treat acute liver failure.

外文关键词：

Liver failureLiver regenerationTranscription regulationTranscription factorHepatocytesPhosphatidic acidPhospholipase d2Translational medicine

作者：

Jiawen Zhou、Xinyue Sun、Xuelian Chen、Huimin Liu、Xiulian Miao、Yan Guo、Zhiwen Fan、Jie Li、Yong Xu、Zilong Li

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作者单位：

State Key Laboratory of Natural Medicines,Department of Pharmacology,China Pharmaceutical University,Nanjing 211198,China

Institute of Biomedical Research,Liaocheng University,Liaocheng 252200,China

Department of Pathology,Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School,Nanjing 210008,China

Department of Infectious Diseases,Nanjing Drum Tower Hospital Affiliated with Nanjing University Medical School,Nanjing 210008,China

Institute of Viruses and Infectious Diseases,Nanjing University,Nanjing 210008,China

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基金：

国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金江苏省自然科学基金

项目编号：

82200684821210018172500181700554BK20221032

出版年：

2024

DOI：

10.1016/j.apsb.2023.10.011

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(1)

参考文献量67