scholarly journals Hepatocyte-Specific Ablation of PP2A Catalytic SubunitαAttenuates Liver Fibrosis Progression via TGF-β1/Smad Signaling

2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Na Lu ◽  
Yun Liu ◽  
An Tang ◽  
Lulu Chen ◽  
Dengshun Miao ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Knockout Mice ◽  
Hepatic Injury ◽  
Smooth Muscle Actin ◽  
Hepatocyte Proliferation ◽  
Mice Model ◽  
Smad Signaling ◽  
Physiological Processes ◽  
Smad Phosphorylation ◽  
Chronic Hepatic Injury

Protein phosphatase 2A (PP2A), a family of the major serine/threonine phosphatases in cells, regulates many aspects of physiological processes. However, isoform-specific substrates and the biological role of each specific member of the PP2A family remain largely unknown. In this study, we investigated whether PP2A catalytic subunit Cα(PP2Acα) is involved in chronic hepatic injury and fibrosis. A hepatocyte-specific PP2Acαablation mice model was established to examine the effect of PP2Acαon carbon tetrachloride- (CCl4-) induced chronic hepatic injury and fibrosis. Our results showed that PP2Acαknockout mice were less susceptible to chronic CCl4-induced liver injury as evidenced by lower levels of serum alanine aminotransferase and aspartate aminotransferase, decreased hepatocyte proliferation, and increased rate of apoptotic removal of the injured hepatocytes. PP2Acαknockout mice also displayed a lesser extent of liver fibrosis as a significant decrease in the proportion ofα-smooth muscle actin-expressing cells and collagen deposition was observed in their liver tissues. Furthermore, the levels of serum TGF-β1 and hepatocytic Smad phosphorylation were reduced in the PP2Acαknockout mice. These data suggest that hepatocyte-specific ablation of PP2Acαprotects against CCl4-induced chronic hepatic injury and fibrogenesis and the protective effect is mediated at least partially through the impaired TGF-β1/Smad signaling.

Transforming growth factor-β2-mediated mesenchymal transition in lens epithelial cells is repressed in the absence of RAGE

2021 ◽  
Vol 478 (12) ◽  
pp. 2285-2296
Author(s):  
Mi-Hyun Nam ◽  
Mina B. Pantcheva ◽  
Johanna Rankenberg ◽  
Ram H. Nagaraj
Keyword(s):  
Growth Factor ◽  
Epithelial Cells ◽  
Knockout Mice ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Lens Epithelial Cells ◽  
Wild Type ◽  
Mesenchymal Transition ◽  
Smad Signaling ◽  
Transforming Growth Factor Β2

Transforming growth factor-β2 (TGFβ2)-mediated epithelial to mesenchymal transition (EMT) in lens epithelial cells (LECs) has been implicated in fibrosis associated with secondary cataracts. In this study, we investigated whether the receptor for advanced glycation end products (RAGE) plays a role in TGFβ2-mediated EMT in LECs. Unlike in the LECs from wild-type mice, TGFβ2 failed to elicit an EMT response in LECs from RAGE knockout mice. The lack of RAGE also diminished TGFβ2-mediated Smad signaling. In addition, treatment with TGFβ2 increased IL-6 levels in LECs from wild-type mice but not in those from RAGE knockout mice. Treatment of human LECs with the RAGE inhibitor FPS-ZM1 reduced TGFβ2-mediated Smad signaling and the EMT response. Unlike that in wild-type lenses, the removal of fiber cell tissue in RAGE knockout lenses did not result in elevated levels of α-smooth muscle actin (α-SMA), fibronectin (FN), and integrin β1 in capsule-adherent LECs. Taken together, these results suggest that TGFβ2 signaling is intricately linked to RAGE. Targeting RAGE could be explored as a therapeutic strategy against secondary cataracts.

scholarly journals Exosomal miR-500 Derived From Lipopolysaccharide-Treated Macrophage Accelerates Liver Fibrosis by Suppressing MFN2

2021 ◽  
Vol 9 ◽  
Author(s):  
Lisha Chen ◽  
Yan Huang ◽  
Zhixi Duan ◽  
Peiqi Huang ◽  
Hongbing Yao ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Cancer ◽  
Mouse Model ◽  
Immune Cells ◽  
Hepatic Injury ◽  
Stellate Cell ◽  
Activated Macrophages ◽  
Hepatic Macrophages ◽  
Chronic Hepatic Injury ◽  
Serum Exosomes

Liver fibrosis is an outcome of chronic hepatic injury, which can eventually result in cirrhosis, liver failure, and even liver cancer. The activation of hepatic stellate cell (HSC) is a prominent driver of liver fibrosis. Recently, it has been found that the crosstalk between HSCs and immune cells, including hepatic macrophages, plays an important role in the initiation and development of liver fibrosis. As a vital vehicle of intercellular communication, exosomes transfer specific cargos into HSCs from macrophages. Here, we show that exosomes derived from lipopolysaccharide (LPS)-treated macrophages has higher expression level of miR-500. And overexpression or inhibition of miR-500 in macrophage exosomes could promote or suppress HSC proliferation and activation. Treatment of exosomes with miR-500 overexpression can accelerate liver fibrosis in CCl4-induced liver fibrosis mouse model. miR-500 promotes HSC activation and liver fibrosis via suppressing MFN2. Moreover, miR-500 in serum exosomes could be a biomarker for liver fibrosis. Taken together, exosomal miR-500 derived from LPS-activated macrophages promotes HSC proliferation and activation by targeting MFN2 in liver fibrosis.

scholarly journals Long-Term Aspartame Administration Leads to Fibrosis, Inflammasome Activation, and Gluconeogenesis Impairment in the Liver of Mice

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 82
Author(s):  
Isabela A. Finamor ◽  
Caroline A. Bressan ◽  
Isabel Torres-Cuevas ◽  
Sergio Rius-Pérez ◽  
Marcelo da Veiga ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Damage ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Elevated Serum ◽  
Inflammasome Activation ◽  
Related Factor ◽  
Type I ◽  
Artificial Sweetener

Background: Aspartame is an artificial sweetener used in foods and beverages worldwide. However, it is linked to oxidative stress, inflammation, and liver damage through mechanisms that are not fully elucidated yet. This work aimed to investigate the effects of long-term administration of aspartame on the oxidative and inflammatory mechanisms associated with liver fibrosis progression in mice. Methods: Mice were divided into two groups with six animals each: control and aspartame. Aspartame (80 mg/kg, via oral) or vehicle was administrated for 12 weeks. Results: Aspartame caused liver damage and elevated serum transaminase levels. Aspartame also generated liver fibrosis, as evidenced by histology analysis, and pro-fibrotic markers’ upregulation, including transforming growth factor β 1, collagen type I alpha 1, and alpha-smooth muscle actin. Furthermore, aspartame reduced nuclear factor erythroid 2-related factor 2 (Nrf2) activation and enzymatic antioxidant activity and increased lipid peroxidation, which triggered NOD-like receptor containing protein 3 (NLRP3) inflammasome activation and p53 induction. Furthermore, aspartame reduced peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) levels, possibly through p53 activation. This PGC-1α deficiency could be responsible for the changes in lipid profile in serum, total lipid accumulation, and gluconeogenesis impairment in liver, evidenced by the gluconeogenic enzymes’ downregulation, thus causing hypoglycemia. Conclusions: This work provides new insights to understand the mechanisms related to the adverse effects of aspartame on liver tissue.

scholarly journals Inflammasome-mediated regulation of hepatic stellate cells

2009 ◽  
Vol 296 (6) ◽  
pp. G1248-G1257 ◽  
Author(s):  
Azuma Watanabe ◽  
Muhammad Adnan Sohail ◽  
Dawidson Assis Gomes ◽  
Ardeshir Hashmi ◽  
Jun Nagata ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Immune Cells ◽  
Hepatic Stellate Cells ◽  
Smooth Muscle Actin ◽  
Stellate Cells ◽  
Inflammasome Activation ◽  
Cellular Injury ◽  
Wild Type ◽  
Primary Mouse ◽  
Msu Crystals

The inflammasome is a cytoplasmic multiprotein complex that has recently been identified in immune cells as an important sensor of signals released by cellular injury and death. Analogous to immune cells, hepatic stellate cells (HSC) also respond to cellular injury and death. Our aim was to establish whether inflammasome components were present in HSC and could regulate HSC functionality. Monosodium urate (MSU) crystals (100 μg/ml) were used to experimentally induce inflammasome activation in LX-2 and primary mouse HSC. Twenty-four hours later primary mouse HSC were stained with α-smooth muscle actin and visualized by confocal microscopy, and TGF-β and collagen1 mRNA expression was quantified. LX-2 cells were further cultured with or without MSU crystals for 24 h in a transwell chemotaxis assay with PDGF as the chemoattractant. We also examined inhibition of calcium (Ca2+) signaling in LX-2 cells treated with or without MSU crystals using caged inositol 1,4,5-triphosphate (IP3). Finally, we confirmed an important role of the inflammasome in experimental liver fibrosis by the injection of carbon tetrachloride (CCl4) or thioacetamide (TAA) in wild-type mice and mice lacking components of the inflammasome. Components of the inflammasome are expressed in LX-2 cells and primary HSC. MSU crystals induced upregulation of TGF-β and collagen1 mRNA and actin reorganization in HSCs from wild-type mice but not mice lacking inflammasome components. MSU crystals inhibited the release of Ca2+ via IP3 in LX-2 cells and also inhibited PDGF-induced chemotaxis. Mice lacking the inflammasome-sensing and adaptor molecules, NLRP3 and apoptosis-associated speck-like protein containing CARD, had reduced CCl4 and TAA-induced liver fibrosis. We concluded that inflammasome components are present in HSC, can regulate a variety of HSC functions, and are required for the development of liver fibrosis.

Piceatannol increases the expression of hepatocyte growth factor and IL-10 thereby protecting hepatocytes in thioacetamide-induced liver fibrosis

2016 ◽  
Vol 94 (7) ◽  
pp. 779-787 ◽  
Author(s):  
Hazem Abd-Elgawad ◽  
Nashwa Abu-Elsaad ◽  
Amr El-Karef ◽  
Tarek Ibrahim
Keyword(s):  
Growth Factor ◽  
Liver Fibrosis ◽  
Liver Function ◽  
Hepatocyte Growth Factor ◽  
Transforming Growth Factor ◽  
Histopathological Examination ◽  
Smooth Muscle Actin ◽  
Interleukin 10 ◽  
Hepatocyte Growth ◽  
Inflammatory Effect

Piceatannol is a polyphenolic analog of resveratrol that selectively inhibits the non-receptor tyrosine kinase-Syk. This study investigates the potential ability of piceatannol to attenuate liver fibrosis and protect hepatocytes from injury. Thioacetamide was injected in adult male mice (100 mg/kg, i.p., 3 times/week) for 8 weeks. Piceatannol (1 or 5 mg/kg per day) was administered by oral gavage during the last 4 weeks. Liver function biomarkers, tissue malondialdehyde (MDA), cytokeratin-18 (CK18), hepatocyte growth factor (HGF), and interleukin-10 (IL-10) were measured. Necroinflammation, fibrosis, expression of transforming growth factor (TGF)-β1, and α-smooth muscle actin (SMA) were scored by histopathological examination and immunohistochemistry. Obtained results showed ability of piceatannol (1 mg/kg) to restore liver function and reduce inflammation. It significantly (p < 0.001) reduced MDA, CK18, TGF-β1, and α-SMA expression, and increased HGF and IL-10. It can be concluded that piceatannol at low dose can inhibit TGF-β1 induced hepatocytes apoptosis and exerts an anti-inflammatory effect attenuating fibrosis progression.

scholarly journals Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism

2018 ◽  
Vol 51 (5) ◽  
pp. 2111-2122 ◽  
Author(s):  
Yi-Bing Hu ◽  
Xiao-Ting Ye ◽  
Qing-Qing Zhou ◽  
Rong-Quan Fu
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Hepatic Fibrosis ◽  
Transforming Growth Factor ◽  
Histopathological Examination ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Mrna Levels ◽  
Alpha Smooth Muscle Actin

Background/Aims: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. Methods: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-β (TGF-β) and in mice treated with carbon tetrachloride (CCl4), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. Results: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl4 model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. Conclusion: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway.

scholarly journals YAP Activation and Implications in Patients and a Mouse Model of Biliary Atresia

2021 ◽  
Vol 8 ◽  
Author(s):  
Chao Zheng ◽  
Jiaqian Luo ◽  
Yifan Yang ◽  
Rui Dong ◽  
Fa-Xing Yu ◽  
...  
Keyword(s):  
Bile Duct ◽  
Liver Fibrosis ◽  
Mouse Model ◽  
Biliary Atresia ◽  
Signaling Pathway ◽  
Target Genes ◽  
Hippo Signaling ◽  
Mice Model ◽  
Hippo Signaling Pathway ◽  
Ductal Cells

Background and Aim: Biliary atresia (BA), an inflammatory destruction of the bile ducts, leads to liver fibrosis in infants and accounts for half of cases undergoing pediatric liver transplantation. Yes-associated protein (YAP), an effector of the Hippo signaling pathway, is critical in maintaining identities of bile ductal cells. Here, we evaluated the expression of YAP and YAP target genes in BA livers and a rhesus rotavirus (RRV)-induced BA mice model.Methods: Liver specimens collected from 200 BA patients were compared with those of 30 non-BA patients. Model mice liver tissues were also collected. The expression of YAP and YAP target genes were measured by transfection, RNA-seq, immunohistochemistry, immunoblot, and quantitative PCR. Masson's trichrome staining and the Biliary Atresia Research Consortium (BARC) system were utilized to score liver fibrosis status.Results: The expression of YAP is elevated and positively correlated with fibrosis in BA livers. Moreover, ANKRD1, which is identified as the target gene of YAP, is also highly expressed in BA livers. Consistent with clinical data, YAP and ANKRD1 are significantly upregulated in RRV-induced BA mouse model.Conclusions: YAP expression is closely correlated with the bile duct hyperplasia and liver fibrosis, and may serve as an indicator for liver fibrosis and BA progression. This study indicates an involvement of the Hippo signaling pathway in the development of BA, and the YAP induced ANKRD1 expression may also be related to bile duct hyperplasia in BA. This provides a new direction for more in-depth exploration of the etiology and pathogenesis of biliary atresia.

Sign in / Sign up

Export Citation Format

Share Document