scholarly journals Alleviation of Carbon-Tetrachloride-Induced Liver Injury and Fibrosis by Betaine Supplementation in Chickens

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Meng-Tsz Tsai ◽  
Ching-Yi Chen ◽  
Yu-Hui Pan ◽  
Siou-Huei Wang ◽  
Harry J. Mersmann ◽  
...  
Keyword(s):  
Carbon Tetrachloride ◽  
Liver Fibrosis ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Food Component ◽  
Metabolic Functions ◽  
Hepatocyte Necrosis

Betaine is a food component with well-reported hepatoprotection effects. However, the effects and mechanisms of betaine on liver fibrosis development are still insufficient. Because metabolic functions of chicken and human liver is similar, we established a chicken model with carbon Tetrachloride- (CCl4-) induced fibrosis for studying antifibrotic effect of betainein vivoandin vitro. Two-week-old male chicks were supplemented with betaine (1%, w/v) in drinking water for 2 weeks prior to the initiation of CCl4treatment (i.p.) until sacrifice. Primary chicken hepatocytes were treated with CCl4and betaine to mimic thein vivosupplementation. The supplementation of betaine significantly alleviated liver fibrosis development along with the inhibition of lipid peroxidation, hepatic inflammation cytokine, and transforming growth factor-β1 expression levels. These inhibitive effects were also accompanied with the attenuation of hepatic stellate cell activation. Furthermore, ourin vitrostudies confirmed that betaine provides antioxidant capacity for attenuating the hepatocyte necrosis by CCl4. Altogether, our results highlight the antioxidant ability of betaine, which alleviates CCl4-induced fibrogenesis process along with the suppression of hepatic stellate cells activation. Since betaine is a natural compound without toxicity, we suggest betaine can be used as a potent nutritional or therapeutic factor for reducing liver fibrosis.

scholarly journals Targeting Follistatin like 1 ameliorates liver fibrosis induced by carbon tetrachloride through TGF-β1-miR29a in mice

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Xin-Yi Xu ◽  
Yan Du ◽  
Xue Liu ◽  
Yilin Ren ◽  
Yingying Dong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Neutralizing Antibody ◽  
Transforming Growth Factor Β1 ◽  
Chemokine Ligand ◽  
Tgf Β1

Abstract Background Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-β1 (TGF-β1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. Methods Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-β1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. Results Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-β1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-β1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. Conclusions Our data suggests TGF-β1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis. Graphical abstract

scholarly journals Dioscin alleviates alcoholic liver fibrosis by attenuating hepatic stellate cell activation via the TLR4/MyD88/NF-κB signaling pathway

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Min Liu ◽  
Youwei Xu ◽  
Xu Han ◽  
Lianhong Yin ◽  
Lina Xu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathway ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Pyrrolidine Dithiocarbamate ◽  
Type I ◽  
Tgf Β1

Abstract The present work aimed to investigate the activities and underlying mechanisms of dioscin against alcoholic liver fibrosis (ALF). In vivo liver fibrosis in mice was induced by an alcoholic liquid diet and in vitro studies were performed on activated HSC-T6 and LX2 cells treated with lipopolysaccharide. Our results showed that dioscin significantly attenuated hepatic stellate cells (HSCs) activation, improved collagen accumulation and attenuated inflammation through down-regulating the levels of myeloid differentiation factor 88 (MyD88), nuclear factor κB (NF-κB), interleukin (IL)-1, IL-6 and tumour necrosis factor-α by decreasing Toll-like receptor (TLR)4 expression both in vivo and in vitro. TLR4 overexpression was also decreased by dioscin, leading to the markedly down-regulated levels of MyD88, NF-κB, transforming growth factor-β1 (TGF-β1), α-smooth muscle actin (α-SMA) and type I collagen (COL1A1) in cultured HSCs. Suppression of cellular MyD88 by ST2825 or abrogation of NF-κB by pyrrolidine dithiocarbamate eliminated the inhibitory effects of dioscin on the levels of TGF-β1, α-SMA and COL1A1. In a word, dioscin exhibited potent effects against ALF via altering TLR4/MyD88/NF-κB signaling pathway, which provided novel insights into the mechanisms of this compound as an antifibrogenic candidate for the treatment of ALF in the future.

scholarly journals Down-Regulation of CXXC5 De-Represses MYCL1 to Promote Hepatic Stellate Cell Activation

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaoyan Wu ◽  
Wenhui Dong ◽  
Ming Kong ◽  
Haozhen Ren ◽  
Jinglin Wang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Zinc Finger Protein ◽  
Stellate Cell ◽  
Underlying Mechanism ◽  
Down Regulation ◽  
Over Expression ◽  
Quiescent Hscs

Liver fibrosis is mediated by myofibroblasts, a specialized cell type involved in wound healing and extracellular matrix production. Hepatic stellate cells (HSC) are the major source of myofibroblasts in the fibrotic livers. In the present study we investigated the involvement of CXXC-type zinc-finger protein 5 (CXXC5) in HSC activation and the underlying mechanism. Down-regulation of CXXC5 was observed in activated HSCs compared to quiescent HSCs both in vivo and in vitro. In accordance, over-expression of CXXC5 suppressed HSC activation. RNA-seq analysis revealed that CXXC5 influenced multiple signaling pathways to regulate HSC activation. The proto-oncogene MYCL1 was identified as a novel target for CXXC5. CXXC5 bound to the proximal MYCL1 promoter to repress MYCL1 transcription in quiescent HSCs. Loss of CXXC5 expression during HSC activation led to the removal of CpG methylation and acquisition of acetylated histone H3K9/H3K27 on the MYCL1 promoter resulting in MYCL1 trans-activation. Finally, MYCL1 knockdown attenuated HSC activation whereas MYCL1 over-expression partially relieved the blockade of HSC activation by CXXC5. In conclusion, our data unveil a novel transcriptional mechanism contributing to HSC activation and liver fibrosis.

scholarly journals Galectin-3 modulates phagocytosis-induced stellate cell activation and liver fibrosis in vivo

2012 ◽  
Vol 302 (4) ◽  
pp. G439-G446 ◽  
Author(s):  
Joy X. Jiang ◽  
Xiangling Chen ◽  
Daniel K. Hsu ◽  
Kornelia Baghy ◽  
Nobuko Serizawa ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
In Vivo Studies ◽  
Enzyme Linked Immunosorbent Assay ◽  
Apoptotic Cells ◽  
Galectin 3

Hepatic stellate cells (HSC), the key fibrogenic cells of the liver, transdifferentiate into myofibroblasts upon phagocytosis of apoptotic hepatocytes. Galectin-3, a β-galactoside-binding lectin, is a regulator of the phagocytic process. In this study, our aim was to study the mechanism by which extracellular galectin-3 modulates HSC phagocytosis and activation. The role of galectin-3 in engulfment was evaluated by phagocytosis and integrin binding assays in primary HSC. Galectin-3 expression was studied by real-time PCR and enzyme-linked immunosorbent assay, and in vivo studies were done in wild-type and galectin-3−/− mice. We found that HSC from galectin-3−/− mice displayed decreased phagocytic activity, expression of transforming growth factor-β1, and procollagen α1(I). Recombinant galectin-3 reversed this defect, suggesting that extracellular galectin-3 is required for HSC activation. Galectin-3 facilitated the αvβ3 heterodimer-dependent binding, indicating that galectin-3 modulates HSC phagocytosis via cross-linking this integrin and enhancing the tethering of apoptotic cells. Blocking integrin αvβ3 resulted in decreased phagocytosis. Galectin-3 expression and release were induced in active HSC engulfing apoptotic cells, and this was mediated by the nuclear factor-κB signaling. The upregulation of galectin-3 in active HSC was further confirmed in vivo in bile duct-ligated (BDL) rats. Galectin-3−/− mice displayed significantly decreased fibrosis, with reduced expression of α-smooth muscle actin and procollagen α1(I) following BDL. In summary, extracellular galectin-3 plays a key role in liver fibrosis by mediating HSC phagocytosis, activation, and subsequent autocrine and paracrine signaling by a feedforward mechanism.

scholarly journals Nicotinamide Riboside, an NAD + Precursor, Reduces Hepatic Stellate Cell Activation and Attenuates Liver Fibrosis in a Diet-induced Mouse Model of Liver Fibrosis (OR24-06-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Tho Pham ◽  
Minkyung Bae ◽  
Mi-Bo Kim ◽  
Yoojin Lee ◽  
Siqi Hu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Energy Expenditure ◽  
Mouse Model ◽  
Cell Activation ◽  
Stellate Cell ◽  
Body Weight Gain ◽  
Nicotinamide Riboside ◽  
Primary Mouse

Abstract Objectives There is limited pharmacological treatment for liver fibrosis, which can result from chronic liver injury. In this study, we investigated the effect of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD) precursor, on the development of liver fibrosis in a diet-induced mouse model of liver fibrosis in vivo and in hepatic stellate cells (HSCs) in vitro. Methods Male C57BL/6 J mice were randomly assigned to three groups: a low-fat control (LF; 6% fat by wt), a high-fat/high-sucrose/high-cholesterol control (HF; 35%/34%/2.0% by wt, n = 13) or a HF diet supplemented with NR at 400 mg/kg/day (HF-NR, n = 14) for 20 weeks. Features of liver fibrosis were assessed by molecular, histological, and biochemical analyses to determine the effect of NR. Metabolic rates, energy expenditure and physical activity were measured using indirect calorimetry. Primary mouse and human HSCs, the primary extracellular matrix-producing cell-type in the liver, were used to determine the anti-fibrogenic effects of NR in vitro. Results HF-NR group had reduced body weight gain, which was attributable to increased energy expenditure. NR supplementation did not affect serum alanine aminotransferase levels and markers of steatosis and inflammation in the liver. However, liver trichrome and picrosirius red staining and total collagen quantification showed significant reductions of collagen by NR. Consistently, hepatic collagen 1a1 mRNA and protein were significantly reduced in the HF-NR group. Liver NAD levels were significantly reduced by HF, but was increased by NR supplementation. RNA-Seq analysis of NAD metabolism genes in quiescent and activated HSCs indicated that NAD levels might be reduced in activated HSCs due to repression of NAD salvage pathway, which regenerates NAD from nicotinamide. Indeed, treatment of primary human and mouse HSCs with NR significantly reduced their activation in vitro. Conclusions NR supplementation prevented the development of liver fibrosis in a diet-induced mouse model of liver fibrosis independent of hepatic steatosis and inflammation. The data suggest that NR may directly reduce HSC activation to exert its anti-fibrotic effect. NR may be developed as a potential preventative for human liver fibrosis. Funding Sources The NIH, USDA Multistate Hatch, and USDA Hatch.

scholarly journals Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaoyan Wu ◽  
Wenhui Dong ◽  
Tianyi Zhang ◽  
Haozhen Ren ◽  
Jinglin Wang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Liver Fibrosis ◽  
Cell Activation ◽  
Serum Response Factor ◽  
Stellate Cell ◽  
Feedforward Loop ◽  
Related Transcription Factor ◽  
Egf Family

Trans-differentiation of quiescent hepatic stellate cells (HSC) into myofibroblast cells is considered the linchpin of liver fibrosis. A myriad of signaling pathways contribute to HSC activation and consequently liver fibrosis. Epidermal growth factor (EGF) family of cytokines signal through the cognate receptor EGFR to promote HSC activation. In the present study we investigated the transcription regulation of epiregulin (EREG), an EGFR ligand, during HSC activation. We report that EREG expression was significantly up-regulated in activated HSCs compared to quiescent HSCs isolated from mice. In addition, there was an elevation of EREG expression in HSCs undergoing activation in vitro. Of interest, deficiency of myocardin-related transcription factor A (MRTF-A), a well-documented regulator of HSC trans-differentiation, attenuated up-regulation of EREG expression both in vivo and in vitro. Further analysis revealed that MRTF-A interacted with serum response factor (SRF) to bind directly to the EREG promoter and activate EREG transcription. EREG treatment promoted HSC activation in vitro, which was blocked by MRTF-A depletion or inhibition. Mechanistically, EREG stimulated nuclear trans-location of MRTF-A in HSCs. Together, our data portray an EREG-MRTF-A feedforward loop that contributes to HSC activation and suggest that targeting the EREG-MRTF-A axis may yield therapeutic solutions against liver fibrosis.

scholarly journals Physalin B attenuates liver fibrosis via suppressing LAP2α-HDAC1 mediated deacetylation of GLI1 and hepatic stellate cell activation

2020 ◽  
Author(s):  
Xiaoyun Zhu ◽  
Shengtao Ye ◽  
Jie Li ◽  
Meihui Zhang ◽  
Yanqiu Zhang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hedgehog Signaling ◽  
Cell Activation ◽  
Stellate Cell ◽  
Histone Deacetylase 1 ◽  
Duct Ligation ◽  
Oncogene Homologue ◽  
Important Therapeutic Target

Background and Purpose: Liver fibrosis is one of the leading causes of morbidity and mortality worldwide of which no acceptable therapy exists. Accumulating evidence supports that glioma-associated oncogene homologue 1(GLI1) is a potentially important therapeutic target for liver fibrosis. This study investigates the antifibrotic activities and potential mechanisms of Physalin B (PB), a natural Solanaceae compound. Experimental Approach: Mice subjected to CCl4 challenge and bile duct ligation were used to study the antifibrotic effects of PB in vivo. Mouse primary hepatic stellate cells (pHSCs) and human HSC line LX‐2 also served as an in vitro liver fibrosis model. Liver fibrogenic genes, GLI1 downstream genes were examined using western blot and real-time PCR analyses. GLI1 acetylation and LAP2α-HDAC1 interaction were analyzed by coimmunoprecipitation. Key Results: In animal models, PB administration attenuated hepatic histopathological injury, collagen accumulation, and reduced the expression of fibrogenic genes. PB dose‐dependently suppressed fibrotic marker expression in LX‐2 cells and mouse pHSCs. Mechanistic studies showed PB inhibited GLI activity in a non-canonical Hedgehog signaling. PB blocked lamina-associated polypeptide 2 α (LAP2α)/ histone deacetylase 1 (HDAC1) complex formation thereby inhibited HDAC1mediated GLI1 deacetylation. PB downregulated the acetylation and expression of GLI1, and subsequently inhibiting HSC activation. Conclusions and Implications: PB exerted potent antifibrotic effects in vitro and in vivo by disrupting the LAP2α/HDAC1 complex, increasing GLI1 acetylation and inactivating GLI1. This indicates that PB may be a potential therapeutic candidate for the treatment of liver fibrosis.

scholarly journals Long Noncoding RNA HOTTIP Promotes Mouse Hepatic Stellate Cell Activation via Downregulating miR-148a

2018 ◽  
Vol 51 (6) ◽  
pp. 2814-2828 ◽  
Author(s):  
Zhiqin Li ◽  
Jia Wang ◽  
Qinglei Zeng ◽  
Chunling Hu ◽  
Jiajia Zhang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Noncoding Rna ◽  
Cell Activation ◽  
Stellate Cell ◽  
Luciferase Reporter ◽  
Fibrotic Liver ◽  
Negative Effect ◽  
High Level

Background/Aims: HOTTIP is a critical modulator in human diseases including liver cancer, but its role and molecular biological mechanisms in liver fibrosis are still unclear. Methods: The expression profile of HOTTIP during the progression of liver fibrosis was detected in human liver samples and in CCl4-treated mice using qRT-PCR. The expressing sh-HOTTIP adenoviral vector was used to reduce HOTTIP levels in vivo. Dual-Luciferase Reporter Assay was performed to validate the interaction between miR-148a and HOTTIP, TGFBR1, or TGFBR2. Results: HOTTIP expressions in fibrotic liver samples and cirrhotic liver samples were significantly upregulated compared with healthy liver controls, and cirrhotic samples exhibited the highest levels of HOTTIP. Moreover, HOTTIP expressions were substantially induced in the liver tissues and hepatic stellate cells (HSC) of CCl4-treated mice. Ad-shHOTTIP delivery could alleviate CCl4- induced liver fibrosis in mice. Down-regulation of HOTTIP inhibited the viability and activation of HSCs in vitro, and HOTTIP negatively regulated miR-148a expression in HSCs. miR-148a had a negative effect on HSC activation by targeting TGFBR1 and TGFBR2. Conclusion: HOTTIP is involved in the progression of liver fibrosis by promoting HSC activation. The high level of HOTTIP downregulates miR-148a, thus to increase the level of TGFBR1 and TGFBR2 and contribute to liver fibrosis.

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