Inhibition of Mastermind-like 1 alleviates liver fibrosis induced by carbon tetrachloride in rats.
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ABSTRACT:
SUBMITTER: Zheng S
PROVIDER: S-EPMC6327369 | biostudies-other | 2018 Nov
REPOSITORIES: biostudies-other
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Inhibition of Mastermind-like 1 alleviates liver fibrosis induced by carbon tetrachloride in rats.
Zheng Shaoping S Chen Yixiong Y Zheng Shaojiang S He Zhihui Z Weng Zhihong Z
Experimental biology and medicine (Maywood, N.J.) 20181001 14
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Project description:Background: Liver fibrosis is a complex inflammatory and fibrogenic process, and the progression of fibrosis leads to cirrhosis. The only therapeutic approaches are the removal of injurious stimuli and liver transplantation. Therefore, the development of anti-fibrotic therapies is desired. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide belonging to the N-acylethanolamines family and contained in foods such as egg yolks and peanuts. PEA has therapeutic anti-inflammatory, analgesic, and neuroprotective effects. However, the effects and roles of PEA in liver fibrosis remain unknown. Here we investigated the therapeutic effects of PEA in rats with liver fibrosis. Methods: We conducted in vitro experiments to investigate the effects of PEA on the activation of hepatic stellate cells (HSCs, LX-2). Liver fibrosis was induced by an intraperitoneal injection of 1.5 mL/kg of 50% carbon tetrachloride twice a week for 4 weeks. Beginning at 3 weeks, PEA (20 mg/kg) was intraperitoneally injected thrice a week for 2 weeks. Then rats were sacrificed and we performed histological and quantitative reverse-transcription polymerase chain reaction analyses. Results: The expression of α-smooth muscle actin (SMA) induced by transforming growth factor (TGF)-β1 in HSCs was significantly downregulated by PEA. PEA treatment inhibited the TGF-β1-induced phosphorylation of SMAD2 in a dose-dependent manner, and upregulated the expression of SMAD7. The reporter gene assay demonstrated that PEA downregulated the transcriptional activity of the SMAD complex upregulated by TGF-β1. Administration of PEA significantly reduced the fibrotic area, deposition of type I collagen, and activation of HSCs and Kupffer cells in rats with liver fibrosis. Conclusion: Activation of HSCs was significantly decreased by PEA through suppression of the TGF-β1/SMAD signaling pathway. Administration of PEA produced significant improvement in a rat model of liver fibrosis, possibly by inhibiting the activation of HSCs and Kupffer cells. PEA may be a potential new treatment for liver fibrosis.
| S-EPMC6053486 | biostudies-literature
Project description:Background and purposeLiver fibrosis is one of the leading causes of morbidity and mortality worldwide with very limited therapeutic options. Given the pivotal role of activated hepatic stellate cells in liver fibrosis, attention has been directed towards the signalling pathways underlying their activation and fibrogenic functions. Recently, the hedgehog (Hh) signalling pathway has been identified as a potentially important therapeutic target in liver fibrosis. The present study was designed to explore the antifibrotic effects of the potent Hh signalling inhibitor, forskolin, and the possible molecular mechanisms underlying these effects.Experimental approachMale Sprague-Dawley rats were treated with either CCl4 and/or forskolin for 6 consecutive weeks. Serum hepatotoxicity markers were determined, and histopathological evaluation was performed. Hepatic fibrosis was assessed by measuring ?-SMA expression and collagen deposition by Masson's trichrome staining and hydroxyproline content. The effects of forskolin on oxidative stress markers (GSH, GPx, lipid peroxides), inflammatory markers (NF-?B, TNF-?, COX-2, IL-1?), TGF-?1 and Hh signalling markers (Ptch-1, Smo, Gli-2) were also assessed.Key resultsHepatic fibrosis induced by CCl4 was significantly reduced by forskolin, as indicated by decreased ?-SMA expression and collagen deposition. Forskolin co-treatment significantly attenuated oxidative stress and inflammation, reduced TGF-?1 levels and down-regulated mRNA expression of Ptch-1, Smo and Gli-2 through cAMP-dependent PKA activation.Conclusion and implicationsIn our model, forskolin exerted promising antifibrotic effects which could be partly attributed to its antioxidant and anti-inflammatory effects, as well as to its inhibition of Hh signalling, mediated by cAMP-dependent activation of PKA.
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Project description:To understand the fibrotic response in the CCl4 induced liver fibrosis model, we performed RNA-seq of liver samples from mice treated with oil or CCl4.
2022-08-19 | GSE207855 | GEO
Project description:Hepatic fibrosis, the major complication of virtually all types of chronic liver damage, usually begins in portal areas, and its severity has been correlated to liver progenitor cells (LPC) expansion from periportal areas, even if the primary targets of injury are intralobular hepatocytes. The aim of this study was to determine the potential fibrogenic role of LPC, using a new experimental model in which rat liver fibrosis was induced by chronic carbon tetrachloride (CCl(4)) administration for 6 weeks, in combination with chronic acetylaminofluorene treatment (AAF), which promotes activation of LPC compartment. Treatment with CCl(4) alone caused a significant increase in serum transaminase activity as well as liver fibrosis initiating around central veins and leading to formation of incomplete centro-central septa with sparse fibrogenic cells expressing ?-smooth muscle actin (?SMA). In AAF/CCl(4)-treated animals, the fibrogenic response was profoundly worsened, with formation of multiple porto-central bridging septa leading to cirrhosis, whereas hepatocellular necrosis and inflammation were similar to those observed in CCl(4)-treated animals. Enhanced fibrosis in AAF/CCl(4) group was accompanied by ductule forming LPC expanding from portal areas, ?SMA-positive cells accumulation in the fibrotic areas and increased expression of hepatic collagen type 1, 3 and 4 mRNA. Moreover, CK19-positive LPC expressed the most potent fibrogenic cytokine transforming growth factor-? (TGF?) without any expression of ?SMA, desmin or fibroblast-specific protein-1, demonstrating that LPC did not undergo an epithelial-mesenchymal transition. In this new experimental model, LPC, by expressing TGF?, contributed to the accumulation of ?SMA-positive myofibroblasts in the ductular reaction leading to enhanced fibrosis but also to disease progression and to a fibrotic pattern similar to that observed in humans.
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Project description:Carbon tetrachloride (CCl4) induced liver fibrosis
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Project description:Background and aimsLiver fibrosis is characterized by the excessive deposition of extracellular matrix (ECM) leading to impaired function and cirrhosis. Previous reports support a role for cadherin-11 (CDH11) in regulating the development of dermal and pulmonary fibrosis. In the current report, the extent to which CDH11 modulates the development of liver fibrosis induced by carbon tetrachloride (CCL4) was assessed.MethodsWild type (WT) and CDH11 deficient (CDH11-/-) mice were treated with CCl4 or vehicle control for 8 weeks to induce liver fibrosis. Liver fibrosis was assessed by histology, collagen content, and RTPCR of fibrotic mediators.ResultsLivers from WT mice treated with CCl4 had increased levels of CDH11 which localized to injured hepatocytes, hepatic stellate cells, and macrophages. Interestingly, CDH11-/- mice had decreased histological evidence of liver fibrosis, collagen deposition, α-smooth muscle actin (α-SMA) accumulation, and mRNA levels of fibrotic mediators such as Col1-α1, Snail, TGF-β and IL-6.ConclusionsThese data demonstrate that CDH11 is increased during liver fibrosis, is an important regulator of liver fibrosis induced by CCL4 and suggest that CDH11 may be a potential therapeutic target for liver fibrosis.
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Project description:Accumulating data demonstrated that hepatic endoplasmic reticulum (ER) stress was involved in the pathogenesis of liver fibrosis. Long-term chronic hepatocyte death contributed to liver fibrosis initiation and progression. Previous researches reported that ER stress sensor inositol-requiring enzyme 1 alpha (IRE1α) was first activated in the process of liver fibrosis. STF-083010 was an IRE1α RNase specific inhibitor. This study aimed to explore the effects of STF-083010 on carbon tetrachloride (CCl4)-induced liver injury and subsequent liver fibrosis. Mice were intraperitoneally (i.p.) injected with CCl4 (0.15 ml/kg) for 8 weeks. In STF-083010+CCl4 group, mice were injected with STF-083010 (30 mg/kg, i.p.), twice a week, beginning from the 6th week after CCl4 injection. CCl4 treatment markedly enhanced the levels of serum ALT, TBIL, DBIL and TBA, and STF-083010 had obviously extenuated CCl4-induced exaltation of ALT, DBIL, and TBA levels. CCl4-induced hepatic hydroxyproline and collagen I, major indicators of liver fibrosis, were alleviated by STF-083010. Additionally, CCl4-induced α-smooth muscle actin, a marker for hepatic stellate cells activation, was obviously attenuated in STF-083010-treated mice. Moreover, CCl4-induced upregulation of inflammatory cytokines was suppressed by STF-083010. Mechanistic exploration found that hepatic miR-122 was downregulated in CCl4-treated mice. Hepatic MCP1, CTGF, P4HA1, Col1α1, and Mmp9, target genes of miR-122, were upregulated in CCl4-treated mice. Interestingly, STF-083010 reversed CCl4-induced hepatic miR-122 downregulation. Correspondingly, STF-083010 inhibited CCl4-induced upregulation of miR-122 target genes. This study provides partial evidence that STF-083010 alleviated CCl4-induced liver injury and thus protected against liver fibrosis associated with hepatic miR-122.
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Project description:Although hepatic fibrosis typically follows chronic inflammation, fibrosis will often regress after cessation of liver injury. In this study, we examined whether liver dendritic cells (DCs) play a role in liver fibrosis regression using carbon tetrachloride to induce liver injury. We examined DC dynamics during fibrosis regression and their capacity to modulate liver fibrosis regression upon cessation of injury. We show that conditional DC depletion soon after discontinuation of the liver insult leads to delayed fibrosis regression and reduced clearance of activated hepatic stellate cells, the key fibrogenic cell in the liver. Conversely, DC expansion induced either by Flt3L (fms-like tyrosine kinase-3 ligand) or adoptive transfer of purified DCs accelerates liver fibrosis regression. DC modulation of fibrosis was partially dependent on matrix metalloproteinase (MMP)-9, because MMP-9 inhibition abolished the Flt3L-mediated effect and the ability of transferred DCs to accelerate fibrosis regression. In contrast, transfer of DCs from MMP-9-deficient mice failed to improve fibrosis regression.Taken together, these results suggest that DCs increase fibrosis regression and that the effect is correlated with their production of MMP-9. The results also suggest that Flt3L treatment during fibrosis resolution merits evaluation to accelerate regression of advanced liver fibrosis.
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