Role In Development Of Liver Fibrosis Research Articles

Unlocking the potential of Mesenchymal stem cells in liver Fibrosis: Insights into the impact of autophagy and aging.

Liver fibrosis is a chronic liver disease characterized by extracellular matrix protein accumulation, potentially leading to cirrhosis or hepatocellular carcinoma. Liver cell damage, inflammatory responses, and apoptosis due to various reasons induce liver fibrosis. Although several treatments, such as antiviral drugs and immunosuppressive therapies, are available for liver fibrosis, they only provide limited efficacy. Mesenchymal stem cells (MSCs) have become a promising therapeutic option for liver fibrosis, because they can modulate the immune response, promote liver regeneration, and inhibit the activation of hepatic stellate cells that contribute to disease development. Recent studies have suggested that the mechanisms through which MSCs gain their antifibrotic properties involve autophagy and senescence. Autophagy, a vital cellular self-degradation process, is critical for maintaining homeostasis and protecting against nutritional, metabolic, and infection-mediated stress. The therapeutic effects of MSCs depend on appropriate autophagy levels, which can improve the fibrotic process. Nonetheless, aging-related autophagic damage is associated with a decline in MSC number and function, which play a crucial role in liver fibrosis development. This review summarizes the recent advancements in the understanding of autophagy and senescence in MSC-based liver fibrosis treatment, presenting the key findings from relevant studies.

Treg cells in the course of chronic hepatitis C virus infection partially normalize in longitudinal observation after successful DAA treatment regardless of hepatic fibrosis stage.

Aim of the studyElevated circulating CD4+ CD25+ Foxp3+ regulatory T cells in patients with chronic hepatitis C (CHC) play an unspecified role in liver fibrosis development. This study aimed to determine whether Treg cells diminish after successful treatment with directacting antivirals (DAA) in patients at different liver fibrosis stages.Material and methodsWe examined 44 patients with CHC (including 29 with liver cirrhosis) seven days before DAA treatment (T0), six months later (T1) and then 22 of them were examined one year (T2) after the first dose. Subsequently, these were compared with 28 volunteers without hepatitis C virus (HCV) (15 with excessive alcohol intake). We assessed the degree of liver fibrosis with FibroScan, aspartate transaminase (AST) to platelet ratio index (APRI), FibroIndex, the Forns index and Fib-4. Circulating Treg cells were measured using flow cytometry.ResultsAll patients achieved a sustained virological response (SVR). After the treatment, all liver fibrosis indicators decreased significantly. The number of circulating Tregs was lower in healthy controls than in patients with CHC (0.0066 × 103 cells/µl and 0.0084 × 103 cells/µl, respectively, p = 0.048). After the treatment we observed an insignificant change to 0.0047 × 103 cells/µl for T1 (p > 0.05) and a significant fall to 0.0041 × 103 cells/µl for T2 (p = 0.03). There was no correlation between the degree of hepatic fibrosis and number of Tregs or post-treatment dynamics.ConclusionsOur study shows that Treg cells normalize gradually over a prolonged period of time after a successful DAA treatment. Their number and dynamics remain independent of liver fibrosis degree. The correlation of this revelation with metabolic disorders, increased susceptibility to infections or persistent risk of HCC remains unclear.

Sulforaphane inhibits the activation of hepatic stellate cell by miRNA-423-5p targeting suppressor of fused.

Liver fibrosis, a common pathological process in chronicliver diseases, is characterized by excessive accumulation of extracellular matrix proteins and considered as a wound healing response to chronic liver injury. Hepatic stellatecell(HSC) activation plays a key role inliverfibrosis development. Previous studies showed that sulforaphane (SFN) has wide protective effects against tissue injury and inflammation. Accumulating evidence has shown that microRNAs play important roles in the development of hepatic fibrosis, some of which have been identified as potential therapeutic targets. This study was conducted to explore the role of SFN in the suppression of HSC activation. Quantitative real-time PCR showed that HSC miR-423-5p levels were up-regulated during HSC activation and down-regulated after SFN administration. Further, transfection of a miR-423-5p mimic demonstrated that inhibition of HSC activation by SFN required down-regulation of miR-423-5p. We showed that suppressor of fused is the direct target of miR-423-5p. SFN may play a role in inhibiting hepatic fibrosis by downregulating miRNA-423-5p. MiRNA-423-5p may be useful as a therapeutic target for treating hepatic fibrosis.

Periostin cross‑reacts with the renin‑angiotensin system during liver fibrosis development.

Periostin is a 90-kDa extracellular matrix protein, which is secreted primarily from fibroblasts and is expressed in the lungs, kidneys and heart valves. Angiotensin II (AT-II) serves pivotal roles in the pathogenesis of several diseases with accompanying fibrosis, including chronic liver diseases. AT-II induces periostin expression by regulating transforming growth factor-β1 (TGF-β1)/Smad signaling during cardiac fibrosis. The aim of the present study was to investigate the interaction between AT-II and periostin during liver fibrosis development. Fischer 344 rats were fed a choline-deficient L-amino-acid (CDAA)-defined diet for 12 weeks to simulate the development of steatohepatitis with liver fibrosis. Losartan, an AT-II type I receptor blocker, was administered to inhibit the effect of AT-II. The therapeutic effect of losartan on hepatic fibrosis development and on periostin expression was then evaluated. Several in vitro experiments were performed to examine the mechanisms underlying the interaction between AT-II and periostin in activated hepatic stellate cells (Ac-HSCs). Treatment with losartan suppressed the development of liver fibrosis induced by the CDAA diet, and reduced hepatic periostin expression. In addition, losartan treatment suppressed hepatic Ac-HSC expansion and hepatic TGF-β1 expression. In vitro analysis using LX2 HSC cells indicated that AT-II can augment TGF-β1 and collagen type I α1 mRNA expression via periostin expression, suggesting that the interaction between AT-II and periostin may serve a role in liver fibrosis development. In conclusion, blockade of AT-II-induced periostin may suppress the progression of liver fibrosis development.

Resveratrol Regulates the Quiescence‐Like Induction of Activated Stellate Cells by Modulating the PPARγ/SIRT1 Ratio

The activation of hepatic stellate cell (HSC), from a quiescent cell featuring cytoplasmic lipid droplets to a proliferative myofibroblast, plays an important role in liver fibrosis development. The GRX line is an activated HSC model that can be induced by all-trans-retinol to accumulate lipid droplets. Resveratrol is known for activating Sirtuin1 (SIRT1), a NAD(+)-dependent deacetylase that suppresses the activity of peroxisome proliferator-activated receptor gamma (PPARγ), an important adipogenic transcription factor involved in the quiescence maintenance of HSC. We evaluated the effects of 0.1 μM of resveratrol in retinol-induced GRX quiescence by investigating the interference of SIRT1 and PPARγ on cell lipogenesis. GRX lipid accumulation was evaluated through Oil-red O staining, triacylglycerides quantification, and [(14)C] acetate incorporation into lipids. mRNA expression and protein content of SIRT1 and PPARγ were measured by RT-PCR and immunoblotting, respectively. Resveratrol-mediated SIRT1 stimuli did not induce lipogenesis and reduced the retinol-mediated fat-storing capacity in GRX. In order to support our results, we established a cell culture model of transgenic super expression of PPARγ in GRX cells (GRXPγ). Resveratrol reduced lipid droplets accumulation in GRXPγ cells. These results suggest that the PPARγ/SIRT1 ratio plays an important role in the fate of HSC. Thus, whenever the PPARγ activity is greater than SIRT1 activity the lipogenesis is enabled.

Cross talk between toll‐like receptor‐4 signaling and angiotensin‐II in liver fibrosis development in the rat model of non‐alcoholic steatohepatitis

The innate immune system, including toll-like receptor-4 (TLR4) signaling cascade and angiotensin-II (AT-II) play important roles in the progression of liver fibrosis development; the cross talk between TLR4 and AT-II has not been elucidated yet. The aim of the current study was to elucidate the effect of AT-II type 1 receptor blocker (ARB), on the liver fibrosis development, especially in conjunction with the interaction of TLR4 and AT-II in the rat model of non-alcoholic steatohepatitis. Fischer 344 rats were fed a choline-deficient, L-amino-acid-defined diet for 8 weeks and the effects of losartan were elucidated in conjunction with activated hepatic stellate cells (Ac-HSC) activation, TLR4, nuclear factor-κB (NF-κB), and transforming growth factor-β (TGF-β) expressions. In vitro study was carried out to elucidate the effect of AT-II on several indices including TLR4, myeloid differentiation factor 88, NF-κB, and TGF-β expressions in the rat HSC. ARB markedly inhibited liver fibrosis development along with suppression of the number of Ac-HSC and TGF-β. These inhibitory effects of ARB were almost in parallel with suppression of the hepatic TLR4 and NF-κB expressions. This in vitro study showed that AT-II significantly augmented the TLR4 expression in a dose- and time-dependent manner via AT-II type 1 receptor in the Ac-HSC. AT-II also augmented the lipopolysaccharide-induced myeloid differentiation factor 88 (MyD88), NF-κB, and TGF-β and these increments were attenuated by treatment with ARB. These studies indicated that the cross talk between TLR4 signaling cascade and AT-II plays a pivotal role in liver fibrosis development in non-alcoholic steatohepatitis.

Crosstalk between high-molecular-weight adiponectin and T-cadherin during liver fibrosis development in rats

Adiponectin, a circulating adipocyte-derived secretory protein, reportedly plays an important role in liver fibrosis development, although the biological role of adiponectin in liver fibrogenesis is still controversial. Adiponectin is present in the serum as three oligometric complexes; namely, high-, middle-, and low-molecular weight (HMW, MMW, and LMW, respectively). Adiponectin exerts different biological activities in an oligomerization-dependent manner. The aim of our current study was to examine the alteration of each isoform of adiponectin and its receptors (AdipoR1, AdipoR2, and T-cadherin) during the choline-deficient L-amino acid-defined (CDAA) diet-induced rat liver fibrosis development. We also elucidated the methylation status of all receptors. The serum level of total adiponectin significantly increased during the liver fibrosis development. Among the three isoforms, only HMW adiponectin was significantly up-regulated whereas MMW and LMW were not. The expression of T-cadherin, which exclusively binds with HMW adiponectin, was significantly augmented as well. The AdipoR2 expression was markedly decreased and showed no marked difference from that of AdipoR1. No obvious methylation change was observed in all three receptors, suggesting that another mechanism is involved in the alteration of receptor gene expression. Collectively, since the specific ligand and receptor were augmented together, crosstalk between HMW adiponectin and T-cadherin may play an important role during liver fibrosis development in rats.

Blockade of renin–angiotensin system in antifibrotic therapy

Recent studies have shown that the renin-angiotensin system (RAS) plays a pivotal role in liver fibrosis. An intrahepatic RAS is expressed in chronically damaged livers, and angiotensin-II (AT-II) reportedly stimulates contraction and proliferation of the activated hepatic stellate cells (Ac-HSC), and increases the transforming growth factor-beta (TGF-beta) expression through angiotensin type-I receptors (AT1-R). Some studies have demonstrated that the clinically used angiotensin-converting enzyme (ACE) inhibitor (ACE-I), and AT1-R blockers (ARB) significantly attenuated experimental liver fibrosis along with suppression of the Ac-HSC and hepatic TGF-beta expression. Angiotensin-II also stimulates the tissue inhibitor of metalloproteinases-1 (TIMP-1) in a dose- and time-dependent manner via protein kinase-C as an intracellular signaling cascade in the Ac-HSC, and these effects are completely suppressed by ARB. Combination treatment with low-dose interferon (IFN) and ACE-I exerts a stronger inhibitory effect than either single agent on its own. In humans it has been reported that ARB markedly improved the liver fibrosis score and TGF-beta expression in patients with chronic hepatitis C and non-alcoholic steatohepatitis. Serum fibrosis markers also significantly improved by treatment with low-dose IFN and ACE-I in patients with chronic hepatitis C, refractory to IFN monotherapy. Collectively, these data suggest that the interaction between AT-II and AT1-R plays a pivotal role in liver fibrosis development. Because both ACE-I and ARB are widely used in clinical practice without serious side-effects, these drugs in combination with IFN may provide a new strategy for antifibrosis therapy.

Angiotensin-II and vascular endothelial growth factor interaction plays an important role in rat liver fibrosis development

Both angiotensin-II (AT-II) and vascular endothelial growth factor (VEGF) have been shown to play important roles in the progression of liver fibrosis. However, the interaction of AT-II with VEGF in the liver fibrosis has not been elucidated yet. The aim of the current study was to elucidate a possible association between these molecules, especially in conjunction with the hepatic stellate cells (HSC). The effect of AT-II type 1 receptor blocker (ARB) was assessed on several indices of choline-deficient l-amino acid-defined (CDAA)-induced liver fibrogenesis. This ARB significantly suppressed liver fibrosis development along with suppression of the VEGF expression and neovascularization in the liver. In the cultured activated HSC, AT-II induced VEGF in a dose- and time-dependent manner. ARB and LY333531, a protein kinase C (PKC) inhibitor, attenuated this augmentation. These results indicated that AT-II and VEGF interaction played an important role in liver fibrosis development, and that in the activated HSC, AT-II utilized type 1 receptor and PKC as an intracellular signaling pathway to induce VEGF.

Angiotensin-II induces the tissue inhibitor of metalloproteinases-1 through the protein kinase-C signaling pathway in rat liver fibrosis development

It has been shown that tissue inhibitor of metalloproteinases-1 (TIMP-1) plays an important role in the progression of liver fibrosis. TIMP-1 gene expression is regulated by several factors in vivo. Among them, angiotensin-II (AT-II) induces TIMP-1 in endothelial cells (EC) in vitro, however, the interaction between these molecules in liver fibrogenesis has not yet been elucidated. The aim of this study was to examine a possible association between TIMP-1 and AT-II both in vitro and in vivo using the clinically available angiotensin-I converting enzyme (ACE) inhibitor, perindopril (PE), and the AT-II type 1 receptor blocker (ARB), candesartan (CA). In cultured activated hepatic stellate cells (HSC), AT-II increased TIMP-1 in a dose- and time-dependent manner. CA and LY 333531, the protein kinase C (PKC) inhibitor, blocked this augmentation in a dose-dependent manner. In the CCl 4- and pig serum-induced rat liver fibrosis model, a clinically comparable low dose of PE and CA significantly suppressed liver fibrosis development associated with the suppression of TIMP-1 expression in the liver. AT-II induces TIMP-1 via type 1 receptor and PKC as an intracellular signaling pathway in activated HSC. These results suggested that the AT-II-induced TIMP-1 plays an important role in liver fibrosis development.

Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats

The renin-angiotensin system (RAS) is frequently activated in patients with chronic liver diseases. Angiotensin-II (AT-II) has been suggested to play an important role in liver fibrogenesis. It induces hepatic stellate cell (HSC) proliferation and up-regulates the transforming growth factor beta(1) (TGF-beta(1)) expression via AT-II type 1 receptor (AT(1)-R) in vitro. The aim of the present study was to examine the in vivo effect of candesartan (CA), a clinically used AT(1)-R blocker (ARB), and perindopril (PE), an angiotensin-converting enzyme (ACE) inhibitor (ACE-I), on pig serum-induced liver fibrosis development in rats. The clinically available comparable doses of CA and PE significantly attenuated the fibrosis development. These inhibitory effects of PE and CA were also found in the on-going liver fibrosis model. The hepatic hydroxyproline and serum fibrosis markers were significantly suppressed by CA and PE treatment. Furthermore, the alpha smooth muscle actin (alpha-SMA) positive cells in number were markedly suppressed by CA and PE treatment. Similarly, the hepatic TGF-beta(1) protein and messenger RNA (mRNA) levels were significantly suppressed. Our in vitro study showed that AT-II increased the TGF-beta(1) mRNA expression in the activated HSCs, and this effect was totally blocked by CA. These results suggested that the RAS, especially AT-II and AT(1)-R interaction plays a pivotal role in liver fibrosis development through HSC activation. Because both CA and PE are widely used in clinical practice without serious side effects, these drugs may provide an effective new strategy for anti-liver fibrosis therapy.

Angiotensin-II type 1 receptor interaction is a major regulator for liver fibrosis development in rats

The renin-angiotensin system (RAS) is frequently activated in patients with chronic liver diseases. Angiotensin-II (AT-II) has been suggested to play an important role in liver fibrogenesis. It induces hepatic stellate cell (HSC) proliferation and up-regulates the transforming growth factor β1 (TGF-β1) expression via AT-II type 1 receptor (AT1-R) in vitro. The aim of the present study was to examine the in vivo effect of candesartan (CA), a clinically used AT1-R blocker (ARB), and perindopril (PE), an angiotensin-converting enzyme (ACE) inhibitor (ACE-I), on pig serum-induced liver fibrosis development in rats. The clinically available comparable doses of CA and PE significantly attenuated the fibrosis development. These inhibitory effects of PE and CA were also found in the on-going liver fibrosis model. The hepatic hydroxyproline and serum fibrosis markers were significantly suppressed by CA and PE treatment. Furthermore, the α smooth muscle actin (α-SMA) positive cells in number were markedly suppressed by CA and PE treatment. Similarly, the hepatic TGF-β1 protein and messenger RNA (mRNA) levels were significantly suppressed. Our in vitro study showed that AT-II increased the TGF-β1 mRNA expression in the activated HSCs, and this effect was totally blocked by CA. These results suggested that the RAS, especially AT-II and AT1-R interaction plays a pivotal role in liver fibrosis development through HSC activation. Because both CA and PE are widely used in clinical practice without serious side effects, these drugs may provide an effective new strategy for anti–liver fibrosis therapy.