Impact of lifestyle interventions targeting physical exercise and caloric intake on cirrhosis regression in rats

2021 ◽  
Author(s):  
Erica Lafoz ◽  
Genís Campreciós ◽  
Héctor García-Calderó ◽  
Aina Anton ◽  
Marina Vilaseca ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Metabolic Profile ◽  
Stellate Cell ◽  
Portal Pressure ◽  
Etiological Agent ◽  
Lifestyle Interventions ◽  
Metabolic Disturbances ◽  
Advanced Cirrhosis ◽  
The Impact

In patients, advanced cirrhosis only regresses partially once the etiological agent is withdrawn. Animal models for advanced cirrhosis regression are missing. Lifestyle interventions (LI) have shown to improve steatosis, inflammation, fibrosis and portal pressure in liver disease. We aimed at characterizing cirrhosis regression after etiological agent removal in experimental models of advanced cirrhosis and to study the impact of different LI on it. Advanced cirrhosis was induced in rats either by CCl4 or by thioacetamide (TAA) administration. Systemic and hepatic hemodynamics, liver fibrosis, hepatic stellate cell (HSC) activation, hepatic macrophage infiltration and metabolic profile were evaluated after 48h, 4 weeks or 8 weeks of etiological agent removal. The impact of LI consisting in caloric restriction (CR) or moderate endurance exercise (MEE) during the 8-week regression process was analyzed. The effect of MEE was also evaluated in early cirrhotic and in healthy rats. A significant reduction in portal pressure (PP), liver fibrosis and HSC activation was observed during regression. However, these parameters remained above those in healthy animals. During regression, animals markedly worsened their metabolic profile. CR although preventing those metabolic disturbances did not further reduce PP, hepatic fibrosis or HSC activation. MEE also prevented metabolic disturbances, without enhancing, but even attenuating the reduction of PP, hepatic fibrosis and HSC activation achieved by regression. MEE also worsened hepatic fibrosis in early-TAA cirrhosis and in healthy rats.

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 Gut Microbiome Contributes to Liver Fibrosis Impact on T Cell Receptor Immune Repertoire

2020 ◽  
Vol 11 ◽  
Author(s):  
Qing Liang ◽  
Meina Zhang ◽  
Yudi Hu ◽  
Wei Zhang ◽  
Ping Zhu ◽  
...  
Keyword(s):  
T Cell ◽  
Liver Fibrosis ◽  
T Cell Receptor ◽  
Stellate Cell ◽  
Cell Receptor ◽  
Rrna Gene ◽  
Immune Microenvironment ◽  
Immune Repertoire ◽  
Liver Fibrogenesis ◽  
The Impact

Gut microbiota (GM) modifies the intrahepatic immune microenvironment, but the underlying mechanisms remain poorly understood. Liver fibrosis-associated imprinting is predicted to be reflected in GM. This study investigated the link between GM and the intrahepatic T cell receptor (TCR) immune repertoire (IR), and whether GM modulates the intrahepatic immune microenvironment via TCR IR during liver fibrosis. We analyzed the correlation between GM and TCR IR during liver fibrogenesis. Accordingly, 16S rRNA gene sequencing (16S-seq) and bulk immune repertoire sequencing (IR-seq) were performed to characterize GM and intrahepatic TCR IR. Fecal microbial transplant (FMT) and TCRβ knockout (TcrbKO) mouse models were employed to determine the biological link between GM and TCR IR in liver fibrosis. We found that GM and intrahepatic TCR IR are highly correlated, with both showing reduced diversity and centralized distribution during liver fibrosis. The restoration of normal intestinal microbiota may reshape intrahepatic TCR IR and delay liver fibrosis. Interestingly, TCR IR ablation abrogated the impact of GM on liver fibrogenesis. Furthermore, GM modulated hepatic stellate cell (HSC) activation via TCR IR-mediated intrahepatic immune milieu. Our study demonstrates that GM, which exhibits cross-talk with the intrahepatic TCR IR, influences the intrahepatic immune microenvironment and liver fibrosis progression.

NP603, a novel and potent inhibitor of FGFR1 tyrosine kinase, inhibits hepatic stellate cell proliferation and ameliorates hepatic fibrosis in rats

2011 ◽  
Vol 301 (2) ◽  
pp. C469-C477 ◽  
Author(s):  
Nan Lin ◽  
Si Chen ◽  
Weidong Pan ◽  
Linan Xu ◽  
Kunpeng Hu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Hepatic Fibrosis ◽  
Hepatic Stellate Cell ◽  
Type I Collagen ◽  
Kinase Inhibitor ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Type I ◽  
Promising Therapeutic Approach ◽  
The Impact

Fibroblast growth factor 2 (FGF-2) and its main receptor FGFR1 have been shown to promote hepatic stellate cell (HSC) activation and proliferation. However, scant information is available on the anti-fibrogenic activity of FGFR1 inhibitors. The aim of this study was to assess the impact of a selective FGFR1 tyrosine kinase inhibitor NP603 on HSC proliferation and hepatic fibrosis. We demonstrated that rat primary HSCs secreted significant amounts of FGF-2, and its tyrosine phosphorylation of FGFR1 was attenuated by NP603. NP603 inhibited HSC activaton by measuring the expression of α-smooth muscle actin (α-SMA) and the production of type I collagen using ELISA. Furthermore, NP603 (25 μM) in vitro strongly suppressed HSC growth induced by FGF-2 (10 ng/ml) and FCS. This effect correlated with the suppression of extracellular-regulated kinase (ERK) activity and its downstream targets cyclin D1 and p21. In addition, PO NP603 (20 mg·kg−1·day−1) administration significantly decreased hepatic collagen deposition and α-SMA expression in CCl4-treated rats. Collectively, these studies suggest that selective blocking of the FGFR1-mediated pathway could be a promising therapeutic approach for the treatment of hepatic fibrosis.

scholarly journals Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis

2020 ◽  
Vol 26 (3) ◽  
pp. 280-293 ◽  
Author(s):  
Le Thi Thanh Thuy ◽  
Hoang Hai ◽  
Norifumi Kawada
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Stellate Cells ◽  
Radical Scavenger ◽  
History Of Research ◽  
Duct Ligation ◽  
History Of

Cytoglobin (Cygb), a stellate cell-specific globin, has recently drawn attention due to its association with liver fibrosis. In the livers of both humans and rodents, Cygb is expressed only in stellate cells and can be utilized as a marker to distinguish stellate cells from hepatic fibroblast-derived myofibroblasts. Loss of Cygb accelerates liver fibrosis and cancer development in mouse models of chronic liver injury including diethylnitrosamine-induced hepatocellular carcinoma, bile duct ligation-induced cholestasis, thioacetamide-induced hepatic fibrosis, and choline-deficient L-amino acid-defined diet-induced non-alcoholic steatohepatitis. This review focuses on the history of research into the role of reactive oxygen species and nitrogen species in liver fibrosis and discusses the current perception of Cygb as a novel radical scavenger with an emphasis on its role in hepatic stellate cell activation and fibrosis.

scholarly journals Tunicamycin Induces Hepatic Stellate Cell Apoptosis Through Calpain-2/Ca2 +-Dependent Endoplasmic Reticulum Stress Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Haiying Liu ◽  
Linyu Dai ◽  
Ming Wang ◽  
Fumin Feng ◽  
Yonghong Xiao
Keyword(s):  
Endoplasmic Reticulum ◽  
Liver Fibrosis ◽  
Endoplasmic Reticulum Stress ◽  
Hepatic Fibrosis ◽  
Stellate Cell ◽  
Apoptosis Protein ◽  
Intracellular Ca ◽  
Calpain 2 ◽  
Endoplasmic Reticulum Stress Pathway ◽  
Clinical Prevention

It has been reported that calpain/caspase-mediated apoptosis induced by endoplasmic reticulum stress (ERS) in hepatic stellate cells (HSCs) by previous studies. At present, the activation of HSC is an important cause of liver fibrosis, and the induction of HSC apoptosis plays an irreplaceable role in reversing liver fibrosis. Therefore, it is of great significance to explore mechanisms of action that can induce HSC apoptosis for the reversal of hepatic fibrosis and the clinical prevention and treatment of hepatic-fibrosis-related diseases such as hepatitis, cirrhosis, and liver cancer. In the current study, we demonstrated that tunicamycin (a novel ERS inducer) can induce the apoptosis of HSCs and increase the concentration of intracellular Ca2+ and the expression of ERS protein GRP78, apoptosis protein caspase-12, and Bax, while it can decrease the antiapoptosis protein expression of Bcl-2. Our findings indicate that tunicamycin can induce HSCs apoptosis through calpain-2/Ca2+-dependent ERS pathway.

The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis

Gut ◽  
2017 ◽  
Vol 67 (9) ◽  
pp. 1704-1715 ◽  
Author(s):  
Dai-Min Xiang ◽  
Wen Sun ◽  
Bei-Fang Ning ◽  
Teng-Fei Zhou ◽  
Xiao-Feng Li ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Activation ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Underlying Mechanism ◽  
Alpha Smooth Muscle Actin ◽  
Regulatory Circuit ◽  
Stat3 Phosphorylation ◽  
The Impact

Background and aimsLiver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear.MethodsThe fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism.ResultsExpression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis.ConclusionsIn aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.

scholarly journals Roles of the Hepatic Endocannabinoid and Apelin Systems in the Pathogenesis of Liver Fibrosis

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1311 ◽  
Author(s):  
Pedro Melgar-Lesmes ◽  
Meritxell Perramon ◽  
Wladimiro Jiménez
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Fibrosis ◽  
Molecular Mechanisms ◽  
Stellate Cell ◽  
Healing Process ◽  
Cell Activity ◽  
Signalling Pathways ◽  
Wound Healing Process ◽  
Cellular Mechanisms ◽  
Multiple Cell

Hepatic fibrosis is the consequence of an unresolved wound healing process in response to chronic liver injury and involves multiple cell types and molecular mechanisms. The hepatic endocannabinoid and apelin systems are two signalling pathways with a substantial role in the liver fibrosis pathophysiology—both are upregulated in patients with advanced liver disease. Endogenous cannabinoids are lipid-signalling molecules derived from arachidonic acid involved in the pathogenesis of cardiovascular dysfunction, portal hypertension, liver fibrosis, and other processes associated with hepatic disease through their interactions with the CB1 and CB2 receptors. Apelin is a peptide that participates in cardiovascular and renal functions, inflammation, angiogenesis, and hepatic fibrosis through its interaction with the APJ receptor. The endocannabinoid and apelin systems are two of the multiple cell-signalling pathways involved in the transformation of quiescent hepatic stellate cells into myofibroblast like cells, the main matrix-producing cells in liver fibrosis. The mechanisms underlying the control of hepatic stellate cell activity are coincident despite the marked dissimilarities between the endocannabinoid and apelin signalling pathways. This review discusses the current understanding of the molecular and cellular mechanisms by which the hepatic endocannabinoid and apelin systems play a significant role in the pathophysiology of liver fibrosis.

scholarly journals The Mechanism of Increased Intestinal Palmitic Acids Absorption and The Impact On Hepatic Stellate Cell Activation in Non-Alcoholic Steatohepatitis

2021 ◽  
Author(s):  
Masakazu Hanayama ◽  
Yasunori Yamamoto ◽  
Hiroki Utsunomiya ◽  
Osamu Yoshida ◽  
Liu Shuang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Portal Vein ◽  
Intestinal Absorption ◽  
Stellate Cell ◽  
Mrna Levels ◽  
Alcoholic Fatty Liver ◽  
Nash Model ◽  
Alcoholic Steatohepatitis ◽  
The Impact ◽  
Palmitic Acids

Abstract Dietary palmitic acids (PAs) promote liver fibrosis in patients with non-alcoholic steatohepatitis (NASH). This study aimed to clarify the intestinal absorption kinetics of dietary PAs and the effect of trans-portal PAs on the activation of hepatic stellate cells (HSCs) involved in liver fibrosis in patients with NASH. First, we found that the concentration of blood PAs after meals was significantly increased in NASH patients compared to control patients (P < 0.01). Second, gene expressions associated with fat absorption and chylomicron formation, such as CD36 and MTP, were significantly increased in the intestine of the NASH model rats fed a high-fat-cholesterol diet compared to control rats. Furthermore, portal PA levels after meals in the NASH model rats were significantly higher compared to control and non-alcoholic fatty liver (NAFL) rats (P<0.01). Third, PA injection via the portal vein to the liver in control rats increased the mRNA levels associated with the activation of HSCs and the expression of α-SMA in liver tissues. Our study showed an increased intestinal absorption of dietary-derived PA in NASH. The rapid increase in PAs via the portal vein to the liver may activate HSCs and affect the development of liver fibrosis in NASH.

scholarly journals Indole-3-Propionic Acid, a Gut-Derived Tryptophan Metabolite, Associates with Hepatic Fibrosis

Nutrients ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 3509
Author(s):  
Ratika Sehgal ◽  
Mariana Ilha ◽  
Maija Vaittinen ◽  
Dorota Kaminska ◽  
Ville Männistö ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Propionic Acid ◽  
Hepatic Fibrosis ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Stellate Cell ◽  
Vital Role ◽  
Liver Histology ◽  
Tryptophan Metabolite

Background and Aims: Gut microbiota-derived metabolites play a vital role in maintenance of human health and progression of disorders, including obesity and type 2 diabetes (T2D). Indole-3-propionic acid (IPA), a gut-derived tryptophan metabolite, has been recently shown to be lower in individuals with obesity and T2D. IPA’s beneficial effect on liver health has been also explored in rodent and cell models. In this study, we investigated the association of IPA with human liver histology and transcriptomics, and the potential of IPA to reduce hepatic stellate cell activation in vitro. Methods: A total of 233 subjects (72% women; age 48.3 ± 9.3 years; BMI 43.1 ± 5.4 kg/m2) undergoing bariatric surgery with detailed liver histology were included. Circulating IPA levels were measured using LC-MS and liver transcriptomics with total RNA-sequencing. LX-2 cells were used to study hepatoprotective effect of IPA in cells activated by TGF-β1. Results: Circulating IPA levels were found to be lower in individuals with liver fibrosis compared to those without fibrosis (p = 0.039 for all participants; p = 0.013 for 153 individuals without T2D). Accordingly, levels of circulating IPA associated with expression of 278 liver transcripts (p < 0.01) that were enriched for the genes regulating hepatic stellate cells (HSCs) activation and hepatic fibrosis signaling. Our results suggest that IPA may have hepatoprotective potential because it is able to reduce cell adhesion, cell migration and mRNA gene expression of classical markers of HSCs activation in LX-2 cells (all p < 0.05). Conclusion: The association of circulating IPA with liver fibrosis and the ability of IPA to reduce activation of LX-2 cells suggests that IPA may have a therapeutic potential. Further molecular studies are needed to investigate the mechanisms how IPA can ameliorate hepatic fibrosis.

scholarly journals Resolvin D1 attenuates CCl4 Induced Liver Fibrosis by Inhibiting Autophagy-Mediated HSC activation via AKT/mTOR Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiahuan Li ◽  
Xiaoling Deng ◽  
Shuhan Wang ◽  
Qianqian Jiang ◽  
Keshu Xu
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Hepatic Fibrosis ◽  
Stellate Cell ◽  
Mtor Pathway ◽  
Protective Effects ◽  
Resolvin D1 ◽  
Akt Inhibitor

Resolvin D1 (RvD1) was previously reported to relieve inflammation and liver damage in several liver diseases, but its potential role in liver fibrosis remains elusive. The aim of our study was to investigate the effects and underlying mechanisms of RvD1 in hepatic autophagy in liver fibrosis. In vivo, male C57BL/6 mice were intraperitoneally injected with 20% carbon tetrachloride (CCl4, 5 ml/kg) twice weekly for 6 weeks to establish liver fibrosis model. RvD1 (100 ng or 300 ng/mouse) was added daily in the last 2 weeks of the modeling period. In vitro, lipopolysaccharide (LPS)-activated LX-2 cells were co-treated with increasing concentrations (2.5–10 nM) of RvD1. The degree of liver injury was measured by detecting serum AST and ALT contents and H&amp;E staining. Hepatic fibrosis was assessed by masson's trichrome staining and metavir scoring. The qRT-PCR, western blot, immunohistochemistry, and immunofluorescence were applied to liver tissues or LPS-activated LX-2 cells to explore the protective effects of RvD1 in liver fibrosis. Our findings reported that RvD1 significantly attenuated CCl4 induced liver injury and fibrosis by decreasing plasma AST and ALT levels, reducing collagen I and α-SMA accumulation and other pro-fibrotic genes (CTGF, TIMP-1 and Vimentin) expressions in mouse liver, restoring damaged histological architecture and improving hepatic fibrosis scores. In vitro, RvD1 also repressed the LPS induced LX-2 cells activation and proliferation. These significant improvements mainly attributed to the inhibiting effect of RvD1 on autophagy in the process of hepatic stellate cell (HSC) activation, as demonstrated by decreased ratio of LC3-II/I and elevated p62 after RvD1 treatment. In addition, using AZD5363 (an AKT inhibitor that activates autophagy) and AZD8055 (an mTOR inhibitor, another autophagy activator), we further verified that RvD1 suppressed autophagy-mediated HSC activation and alleviated CCl4 induced liver fibrosis partly through AKT/mTOR pathway. Overall, these results demonstrate that RvD1 treatment is expected to become a novel therapeutic strategy against liver fibrosis.

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