Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles

Liu, Runping; Ding, Mingning; Zheng, Qi; Wu, Jianzhi; Xue, Xiaoyong; Gu, Yiqing; Ma, Bo-ning; Cai, Yajie; Li, Shuo; Su, Lin; Zhang, Luyong; Li, Xiaojiaoyang

doi:10.1038/s41401-021-00843-w

Cited by 27 publications

(19 citation statements)

References 38 publications

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“…Another finding confirmed that liver injury (CCl 4 or acetaminophen) resulted in mitochondrial dysfunction and the subsequent release of mitochondrial DNA from injured hepatocytes to normal hepatocytes and aHSCs through EVs, finally mediating fibrogenic responses in aHSCs. 94 Notably, mesenchymal stem cell (MSC)exosomes alleviated liver fibrosis by triggering HSC ferroptosis mechanistically by promoting ferroptosis-like cell death, mitochondrial dysfunction, and lipid peroxidation in aHSCs. 95 In the future, the direct effect of HSC-derived exosomes on mitochondrial metabolism in HSCs should not be underestimated.…”

Section: Mitochondrial Metabolismmentioning

confidence: 99%

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

Yin¹,

Li²,

Song³

et al. 2022

J Clin Transl Hepatol

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Hepatic stellate cells (HSCs) play an essential role in various liver diseases, and exosomes are critical mediators of intercellular communication in local and distant microenvironments. Cellular crosstalk between HSCs and surrounding multiple tissue-resident cells promotes or inhibits the activation of HSCs. Substantial evidence has revealed that HSC-derived exosomes are involved in the occurrence and development of liver diseases through the regulation of retinoid metabolism, lipid metabolism, glucose metabolism, protein metabolism, and mitochondrial metabolism. HSCderived exosomes are underpinned by vehicle molecules, such as mRNAs and microRNAs, that function in, and significantly affect, the processes of various liver diseases, such as acute liver injury, alcoholic liver disease, nonalcoholic fatty liver disease, viral hepatitis, fibrosis, and cancer. As such, numerous exosomes derived from HSCs or HSCassociated exosomes have attracted attention because of their biological roles and translational applications as potential targets for therapeutic targets. Herein, we review the pathophysiological and metabolic processes associated with HSC-derived exosomes, their roles in various liver diseases and their potential clinical application.

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Section: Mitochondrial Metabolismmentioning

confidence: 99%

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

Yin¹,

Li²,

Song³

et al. 2022

J Clin Transl Hepatol

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“…The transforming growth factor beta (TGF-β) signaling pathway, AKT signaling pathway and hedgehog signaling pathway are dominant pro-fibrotic signaling pathways by regulating the transcription of fibrosis-related genes in livers 22 . According to our latest study, mtDNA-enriched EVs released from oxidative stressed hepatocytes induced by either carbon tetrachloride (CCl 4 ) or acetaminophen directly activated HSCs and drived liver scarring by upregulating the transcription of fibrotic genes including Acta2 , Col1a1 and Fibronectin 5 . Although we did not explicitly investigate how these mtDNA-enriched EVs regulated gene transcription because of the mtDNA loop structure, there are many other studies linking this change to miRNAs, another kind of non-coding RNAs being recognized to regulate a variety of target genes.…”

Section: Hepatocytes-centered Evs Networkmentioning

confidence: 99%

“…Our recent study found that mtDNA-EVs secreted by damaged hepatocytes aggravated hepatocyte death in the CCl 4 -induced hepatic fibrosis mouse model, thus releasing more immunogenic DAMPs and accelerating innate immune response and fibrogenesis in an autocrine manner [5]. However, few studies exist evaluating how damaged liver cells affect other hepatocytes to influence the progression of liver fibrosis, which is worthy of further study.…”

Section: Delivering Evs From Hepatocytes To Hepatocytesmentioning

confidence: 99%

“…Recently, researchers have paid more attention to the pathological communication between different types of cells inside the liver, which can interact with each other and synergistically trigger a distinct cascade of fibrotic responses. Hepatocytes are usually damaged first and spark inflammation by releasing a variety of signaling substances including damage-associated molecular patterns (DAMPs), which further activate resident liver immune cells and recruit bone marrow-derived immune cells into the injured sites 5 . Meanwhile, injured cholangiocytes adjacent to hepatocytes can also release inflammatory cytokines and chemokines and contribute to a pathological reparative reaction 6 .…”

Section: Introductionmentioning

confidence: 99%

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Extracellular vesicles: catching the light of intercellular communication in fibrotic liver diseases

Li¹,

Wu²,

Liu³

et al. 2022

Theranostics

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The increasing prevalence of fibrotic liver diseases resulting from different etiologies has become a major global problem for public health. Fibrotic liver diseases represent a redundant accumulation of extracellular matrix, dysregulation of immune homeostasis and angiogenesis, which eventually contribute to the progression of cirrhosis and liver malignancies. The concerted actions among liver cells including hepatocytes, hepatic stellate cells, kupffer cells, liver sinusoidal endothelial cells and other immune cells are essential for the outcome of liver fibrosis. Recently, a growing body of literature has highlighted that extracellular vesicles (EVs) are critical mediators of intercellular communication among different liver cells either in local or distant microenvironments, coordinating a variety of systemic pathological and physiological processes. Despite the increasing interests in this field, there are still relatively few studies to classify the contents and functions of EVs in intercellular transmission during hepatic fibrogenesis. This review aims to summarize the latest findings with regards to the cargo loading, release, and uptake of EVs in different liver cells and clarify the significant roles of EVs played in fibrotic liver diseases.

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“…Horn et al found that hepatocyte free cholesterol overload can lead to endoplasmic reticulum stress, mitochondrial dysfunction, production of toxic oxysterols and cholesterol crystallization in lipid droplets, which can lead to hepatocyte apoptosis, necrosis or pyroptosis, and activation of HSCs leading to liver fibrosis [6]. Li et al found that the use of carbon tetrachloride (CCl4) or acetaminophen in cultured mouse primary hepatocytes can lead to mitochondrial dysfunction, the release of mitochondrial DNA from damaged hepatocytes to adjacent hepatocytes and HSCs through extracellular vesicles, and mediate activated hepatocyte injury and fibrosis, and pretreatment of mouse primary hepatocytes with tetramethylpyrazine can prevent these pathological effects [7]. Nwaechefu et al found in a rat model induced by CCl4 that Cajanus cajan can protect against liver injury by inhibiting the opening of mitochondrial permeability transition pores, preventing CCl4-induced liver oxidative stress and inhibiting the inflammatory reaction [8].…”

Section: Introductionmentioning

confidence: 99%

Identification of Timm13 protein translocase of the mitochondrial inner membrane as a potential mediator of liver fibrosis based on bioinformatics and experimental verification

Liao

Ruan

et al. 2023

J Transl Med

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Objective To explore the association between translocase of the inner mitochondrial membrane 13 (Timm13) and liver fibrosis. Methods Gene expression profiles of GSE167033 were collected from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) between liver disease and normal samples were analyzed using GEO2R. Gene Ontology and Enrichment function were performed, a protein–protein interaction (PPI) network was constructed via the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), and the hub genes of the PPI network were calculated by MCODE plug-in in Cytoscape. We validated the transcriptional and post-transcriptional expression levels of the top correlated genes using fibrotic animal and cell models. A cell transfection experiment was conducted to silence Timm13 and detect the expression of fibrosis genes and apoptosis genes. Results 21,722 genes were analyzed and 178 DEGs were identified by GEO2R analysis. The top 200 DEGs were selected and analyzed in STRING for PPI network analysis. Timm13 was one of the hub genes via the PPI network. We found that the mRNA levels of Timm13 in fibrotic liver tissue decreased (P < 0.05), and the mRNA and protein levels of Timm13 also decreased when hepatocytes were stimulated with transforming growth factor-β1. Silencing Timm13 significantly reduced the expression of profibrogenic genes and apoptosis related genes. Conclusions The results showed that Timm13 is closely related to liver fibrosis and silencing Timm13 significantly reduced the expression of profibrogenic genes and apoptosis related genes, which will provide novel ideas and targets for the clinical diagnosis and treatment of liver fibrosis.

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Tetramethylpyrazine prevents liver fibrotic injury in mice by targeting hepatocyte-derived and mitochondrial DNA-enriched extracellular vesicles

Cited by 27 publications

References 38 publications

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

Unraveling the Emerging Niche Role of Hepatic Stellate Cell-derived Exosomes in Liver Diseases

Extracellular vesicles: catching the light of intercellular communication in fibrotic liver diseases

Identification of Timm13 protein translocase of the mitochondrial inner membrane as a potential mediator of liver fibrosis based on bioinformatics and experimental verification

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