Browsing by Author "Dou, Longyu"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Knocking out Fkbp51 decreases CCl4-induced liver injury through enhancement of mitochondrial function and Parkin activity
    (Springer Nature, 2024-01-02) Qiu, Bin; Zhong, Zhaohui; Dou, Longyu; Xu, Yuxue; Zou, Yi; Weldon, Korri; Wang, Jun; Zhang, Lingling; Liu, Ming; Williams, Kent E.; Spence, John Paul; Bell, Richard L.; Lai, Zhao; Yong, Weidong; Liang, Tiebing; Medicine, School of Medicine
    Background and aims: Previously, we found that FK506 binding protein 51 (Fkbp51) knockout (KO) mice resist high fat diet-induced fatty liver and alcohol-induced liver injury. The aim of this research is to identify the mechanism of Fkbp51 in liver injury. Methods: Carbon tetrachloride (CCl4)-induced liver injury was compared between Fkbp51 KO and wild type (WT) mice. Step-wise and in-depth analyses were applied, including liver histology, biochemistry, RNA-Seq, mitochondrial respiration, electron microscopy, and molecular assessments. The selective FKBP51 inhibitor (SAFit2) was tested as a potential treatment to ameliorate liver injury. Results: Fkbp51 knockout mice exhibited protection against liver injury, as evidenced by liver histology, reduced fibrosis-associated markers and lower serum liver enzyme levels. RNA-seq identified differentially expressed genes and involved pathways, such as fibrogenesis, inflammation, mitochondria, and oxidative metabolism pathways and predicted the interaction of FKBP51, Parkin, and HSP90. Cellular studies supported co-localization of Parkin and FKBP51 in the mitochondrial network, and Parkin was shown to be expressed higher in the liver of KO mice at baseline and after liver injury relative to WT. Further functional analysis identified that KO mice exhibited increased ATP production and enhanced mitochondrial respiration. KO mice have increased mitochondrial size, increased autophagy/mitophagy and mitochondrial-derived vesicles (MDV), and reduced reactive oxygen species (ROS) production, which supports enhancement of mitochondrial quality control (MQC). Application of SAFit2, an FKBP51 inhibitor, reduced the effects of CCl4-induced liver injury and was associated with increased Parkin, pAKT, and ATP production. Conclusions: Downregulation of FKBP51 represents a promising therapeutic target for liver disease treatment.
  • Thumbnail Image
    Item
    Loss of FKBP5 Affects Neuron Synaptic Plasticity: An Electrophysiology Insight
    (Elsevier, 2019-03) Qiu, Bin; Xu, Yuxue; Wang, Jun; Liu, Ming; Dou, Longyu; Deng, Ran; Wang, Chao; Williams, Kent E.; Stewart, Robert B.; Xie, Zhongwen; Ren, Wei; Zhao, Zhenwen; Shou, Weinian; Liang, Tiebing; Yong, Weidong; Medicine, School of Medicine
    FKBP5 (FKBP51) is a glucocorticoid receptor (GR) binding protein, which acts as a co-chaperone of heat shock protein 90 (HSP90) and negatively regulates GR. Its association with mental disorders has been identified, but its function in disease development is largely unknown. Long-term potentiation (LTP) is a functional measurement of neuronal connection and communication, and is considered one of the major cellular mechanisms that underlies learning and memory, and is disrupted in many mental diseases. In this study, a reduction in LTP in Fkbp5 knockout (KO) mice was observed when compared to WT mice, which correlated with changes to the glutamatergic and GABAergic signaling pathways. The frequency of mEPSCs was decreased in KO hippocampus, indicating a decrease in excitatory synaptic activity. While no differences were found in levels of glutamate between KO and WT, a reduction was observed in the expression of excitatory glutamate receptors (NMDAR1, NMDAR2B and AMPAR), which initiate and maintain LTP. The expression of the inhibitory neurotransmitter GABA was found to be enhanced in Fkbp5 KO hippocampus. Further investigation suggested that increased expression of GAD65, but not GAD67, accounted for this increase. Additionally, a functional GABAergic alteration was observed in the form of increased mIPSC frequency in the KO hippocampus, indicating an increase in presynaptic GABA release. Our findings uncover a novel role for Fkbp5 in neuronal synaptic plasticity and highlight the value of Fkbp5 KO as a model for studying its role in neurological function and disease development.
  • Thumbnail Image
    Item
    Protein phosphatase 5 and the tumor suppressor p53 down-regulate each other's activities in mice
    (American Society for Biochemistry and Molecular Biology, 2018-11-23) Wang, Jun; Shen, Tao; Zhu, Wuqiang; Dou, Longyu; Gu, Hao; Zhang, Lingling; Yang, Zhenyun; Chen, Hanying; Zhou, Qi; Sánchez, Edwin R.; Field, Loren J.; Mayo, Lindsey D.; Xie, Zhongwen; Xiao, Deyong; Lin, Xia; Shou, Weinian; Yong, Weidong; Pediatrics, School of Medicine
    Protein phosphatase 5 (PP5), a serine/threonine phosphatase, has a wide range of biological functions and exhibits elevated expression in tumor cells. We previously reported that pp5-deficient mice have altered ataxia-telangiectasia mutated (ATM)-mediated signaling and function. However, this regulation was likely indirect, as ATM is not a known PP5 substrate. In the current study, we found that pp5-deficient mice are hypersensitive to genotoxic stress. This hypersensitivity was associated with the marked up-regulation of the tumor suppressor tumor protein p53 and its downstream targets cyclin-dependent kinase inhibitor 1A (p21), MDM2 proto-oncogene (MDM2), and phosphatase and tensin homolog (PTEN) in pp5-deficient tissues and cells. These observations suggested that PP5 plays a role in regulating p53 stability and function. Experiments conducted with p53 +/- pp5 +/- or p53 +/- pp5 -/- mice revealed that complete loss of PP5 reduces tumorigenesis in the p53 +/- mice. Biochemical analyses further revealed that PP5 directly interacts with and dephosphorylates p53 at multiple serine/threonine residues, resulting in inhibition of p53-mediated transcriptional activity. Interestingly, PP5 expression was significantly up-regulated in p53-deficient cells, and further analysis of pp5 promoter activity revealed that p53 strongly represses PP5 transcription. Our results suggest a reciprocal regulatory interplay between PP5 and p53, providing an important feedback mechanism for the cellular response to genotoxic stress.