Curcumin Affects Leptin-Induced Expression of Methionine Adenosyltransferase 2A in Hepatic Stellate Cells by Inhibition of JNK Signaling

Pharmacology ◽  
2021 ◽  
pp. 1-9
Author(s):  
Shu Lu ◽  
Hongsheng Zhao ◽  
Yajun Zhou ◽  
Feifan Xu
Keyword(s):  
Dna Methylation ◽  
Liver Fibrosis ◽  
Promoter Activity ◽  
Stellate Cell ◽  
Methionine Adenosyltransferase ◽  
Epigenetic Mechanism ◽  
Obese Patients ◽  
Gene Expressions ◽  
Jnk Signaling ◽  
Liver Fibrogenesis

<b><i>Introduction:</i></b> Obese patients are often accompanied by hyperleptinemia and prone to develop liver fibrosis. Accumulating data including those obtained from human studies suggested the promotion role of leptin in liver fibrosis. The remodeling of the DNA methylation is an epigenetic mechanism for regulating gene expression and is essential for hepatic stellate cell (HSC) activation, a key step in liver fibrogenesis. Leptin increases the expression of methionine adenosyltransferase 2A (MAT2A) which is associated with DNA methylation and HSC activation. Curcumin, an active polyphenol of the golden spice turmeric, inhibits leptin-induced HSC activation and liver fibrogenesis. Thus, the present research aimed to investigate the influence of curcumin on the roles of leptin in MAT2A expression in HSCs. <b><i>Methods:</i></b> The in vivo experiments were conducted by using leptin-deficient obese mice. The gene expressions were examined by Western blot, real-time PCR, promoter activity assay, and immunostaining analysis. <b><i>Results:</i></b> Curcumin reduced leptin-induced MAT2A expression. JNK signaling contributed to leptin-induced increase in MAT2A level, which could be interrupted by curcumin treatment. Curcumin inhibited leptin-induced MAT2A promoter activity by influencing MAT2A promoter fragments between −2,847 bp and − 2,752 bp and between −2,752 bp and +49 bp. The effect of curcumin on leptin-induced MAT2A expression paralleled the reductions in leptin-induced activated HSCs and liver fibrosis. <b><i>Conclusion:</i></b> These results might have implications for curcumin inhibition of the liver fibrogenesis in obese patients with hyperleptinemia.

scholarly journals TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1419 ◽  
Author(s):  
Dewidar ◽  
Meyer ◽  
Dooley ◽  
Meindl-Beinker
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Stellate Cell ◽  
Reactive Oxygen Species Generation ◽  
Mesenchymal Transition ◽  
Therapeutic Benefits ◽  
Liver Fibrogenesis

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment is mainly the removal of the causative factor. Transforming growth factor (TGF)-β is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-β has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-β and its upstream and downstream regulatory mechanisms will help to design better TGF-β based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-β signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-β on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-β. Finally, we discuss new approaches to target the TGF-β pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

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.

Impact on clinical prognosis using DNA methylation of the SLC16A3 promoter and expression of the human lactate transporter MCT4 in renal cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 452-452
Author(s):  
Jens Bedke ◽  
Pascale Fisel ◽  
Stefan Winter ◽  
Stephan Kruck ◽  
Marcus Scharpf ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Protein Expression ◽  
Mrna Expression ◽  
Promoter Activity ◽  
Epigenetic Mechanism ◽  
Monocarboxylate Transporter ◽  
Clinical Prognosis ◽  
Cpg Sites ◽  
Promoter Dna Methylation ◽  
Promoter Dna

452 Background: The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts. Methods: MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n = 482) and DNA methylation (n = 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n = 64). Promoter activity assays were conducted in four RCC cell lines. Results: MCT4 protein expression was upregulated (p < 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (p < 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR = 0.39; 95% confidence interval (CI), 0.24-0.64; P[log-rank] = 1.23e(-04)]. Promoter activity studies confirmed MCT4 regulation by DNA methylation. The significant correlation between MCT4 protein and gene expression or DNA methylation at single CpG sites was validated in a third cohort. Again, higher methylation at individual CpG sites was associated with prolonged survival [HR = 0.05; 95% CI, 0.01-0.40; P[log-rank] = 6.91e(-05)]. Conclusions: This study identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC. First evidence of a biological rationale for prognosis and clinical outcome is supported by this specific SLC16A3 promoter DNA methylation.

Epigenetics in Liver Fibrosis

2017 ◽  
Vol 37 (03) ◽  
pp. 219-230 ◽  
Author(s):  
Veronica Massey ◽  
Joaquin Cabezas ◽  
Ramon Bataller
Keyword(s):  
Dna Methylation ◽  
Liver Fibrosis ◽  
Epigenetic Regulation ◽  
Cell Activation ◽  
Stellate Cell ◽  
Epigenetic Mechanisms ◽  
Epigenetic Landscape ◽  
Chronic Liver Injury ◽  
Novel Biomarkers ◽  
Disease Specific

AbstractLiver fibrosis is a common consequence of chronic liver injury and is a key determinant of liver-associated morbidity and mortality. Identification of new mechanisms of fibrosis, including disease-specific molecular drivers, remains relevant to reveal novel biomarkers and therapeutic targets. Recently, greater accessibility to more advanced molecular methods that can assess changes in epigenetic regulation has stimulated more research investigating the epigenetic landscape of liver fibrosis. Such studies have revealed changes in DNA methylation, histone acetylation, and microRNAs that regulate the fibrogenic response to injury including hepatic stellate cell activation. The aim of this review is to briefly introduce the general mechanisms and epigenetic regulation of liver fibrosis and to familiarize the reader with the chief epigenetic mechanisms implicated as drivers of liver fibrosis.

scholarly journals miR-200c Accelerates Hepatic Stellate Cell-Induced Liver Fibrosis via Targeting the FOG2/PI3K Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-8 ◽  
Author(s):  
Tengfei Ma ◽  
Xiuqin Cai ◽  
Zifeng Wang ◽  
Li Huang ◽  
Chang Wang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Protein Expression ◽  
Stellate Cell ◽  
Smooth Muscle Actin ◽  
Collagen Type I ◽  
Pi3k Pathway ◽  
Type I ◽  
Potential Marker ◽  
Liver Fibrogenesis ◽  
Main Component

Background. Although expression of miR-200s is aberrant in liver fibrosis, its role in liver fibrogenesis still remains unknown. Here, we investigated the role of miR-200c in the activation of human hepatic stellate cells (HSCs) and induction of liver fibrosis. Methods. We engineered human HSCs (LX2 cell line) to stably express miR-200c (LX2-200c) or empty vector control (LX2-nc). Results. miR-200c expression upregulated α-smooth muscle actin (SMA) and vimentin, enhanced HSCs growth and migration, increased expression of collagen type I (a main component of ECM) gene and secretion of epidermal growth factor (EGF), and upregulated the phosphorylation of Akt, a downstream effector of the PI3K pathway. As a target of miR-200s and inhibitor of PI3K pathway, FOG2 protein expression was significantly suppressed in LX2-200c cells. Moreover, LY294002, a highly selective inhibitor of PI3K, blocked phosphorylation of Akt and the effects of miR-200c. Conclusions. These data suggest that miR-200c activates HSCs in liver fibrosis possibly by downregulating FOG2 protein expression and upregulating PI3K/Akt signaling. Autocrine activation of EGF signaling may also be a mechanism of miR-200c-mediated HSCs activation. So miR-200c can be a potential marker for HSCs activation and liver fibrosis progression, as well as a potential target to attenuate liver fibrosis.

scholarly journals Glucose-induced, duration-dependent genome-wide DNA methylation changes in human endothelial cells

2020 ◽  
Vol 319 (2) ◽  
pp. C268-C276
Author(s):  
Erfan Aref-Eshghi ◽  
Saumik Biswas ◽  
Charlie Chen ◽  
Bekim Sadikovic ◽  
Subrata Chakrabarti
Keyword(s):  
Dna Methylation ◽  
Endothelial Cells ◽  
Embryonic Development ◽  
Cellular Differentiation ◽  
Hox Genes ◽  
Transforming Growth Factor ◽  
Umbilical Vein ◽  
Epigenetic Mechanism ◽  
Dna Hypermethylation ◽  
Gene Expressions

DNA methylation, a critical epigenetic mechanism, plays an important role in governing gene expressions during biological processes such as aging, which is well known to be accelerated in hyperglycemia (diabetes). In the present study, we investigated the effects of glucose on whole genome DNA methylation in small [human retinal microvascular endothelial cells (HRECs)] and large [human umbilical vein endothelial cells (HUVECs)] vessel endothelial cell (EC) lines exposed to basal or high glucose-containing media for variable lengths of time. Using the Infinium EPIC array, we obtained 773,133 CpG sites (probes) for analysis. Unsupervised clustering of the top 5% probes identified four distinct clusters within EC groups, with significant methylation differences attributed to EC types and the duration of cell culture rather than glucose stimuli alone. When comparing the ECs incubated for 2 days versus 7 days, hierarchical clustering analyses [methylation change >10% and false discovery rate (FDR) <0.05] identified 17,354 and 128 differentially methylated CpGs for HUVECs and HRECs, respectively. Predominant DNA hypermethylation was associated with the length of culture and was enriched for gene enhancer elements and regions surrounding CpG shores and shelves. We identified 88 differentially methylated regions (DMRs) for HUVECs and 8 DMRs for HRECs (all FDR <0.05). Pathway enrichment analyses of DMRs highlighted involvement of regulators of embryonic development (i.e., HOX genes) and cellular differentiation [transforming growth factor-β (TGF-β) family members]. Collectively, our findings suggest that DNA methylation is a complex process that involves tightly coordinated, cell-specific mechanisms. Such changes in methylation overlap genes critical for cellular differentiation and embryonic development.

Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis

2008 ◽  
Vol 294 (1) ◽  
pp. G39-G49 ◽  
Author(s):  
Jason H. Cheng ◽  
Hongyun She ◽  
Yuan-Ping Han ◽  
Jiaohong Wang ◽  
Shigang Xiong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Wnt Signaling ◽  
Messenger Rna ◽  
Promoter Activity ◽  
Cell Activation ◽  
Therapeutic Potential ◽  
Stellate Cell ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Activation of hepatic stellate cells (HSC), a key event in liver fibrosis, is caused by diminished adipogenic transcription. This study investigated whether Wnt signaling contributes to “antiadipogenic” activation of HSC and liver fibrogenesis. Culture-activated HSC from normal rats and HSC from cholestatic rat livers were examined for expression of Wnt, Frizzled (Fz) receptors, and coreceptors by quantitative PCR. Wnt signaling was assessed by nuclear β-catenin and T cell factor (TCF) promoter activity. Dickkopf-1 (Dkk-1), a Wnt coreceptor antagonist, was transduced by an adenoviral vector to assess the effects of Wnt antagonism on culture activation of HSC and cholestatic liver fibrosis in mice. Messenger RNA for canonical (Wnt3a and 10b) and noncanonical (Wnt4 and 5a) Wnt genes, Fz-1 and 2, and coreceptors [low-density lipoprotein-receptor-related protein (LRP)6 and Ryk] are increased ∼3–12-fold in culture-activated HSC compared with quiescent HSC. The nuclear β-catenin level and TCF DNA binding are markedly increased in activated HSC. TCF promoter activity is stimulated with Wnt1 but inhibited by Chibby, a protein that blocks β-catenin interaction with TCF, and by Dkk-1. Dkk-1 enhances peroxisome proliferator-activated receptor-γ (PPARγ)-driven PPAR response element (PPRE) promoter activity, a key adipogenic transcriptional parameter, abrogates agonist-stimulated contraction, and restores HSC quiescence in culture. High expression of Dkk-1 increases apoptosis of cultured HSC. Expression of Wnt and Fz genes is also induced in HSC isolated from experimental cholestatic liver fibrosis, and Dkk-1 expression ameliorates this form of liver fibrosis in mice. These results demonstrate antiadipogenic Wnt signaling in HSC activation and therapeutic potential of Wnt antagonism for liver fibrosis.

scholarly journals Hepatic Stellate Cell: A Double-Edged Sword in the Liver

2021 ◽  
pp. 821-829
Author(s):  
N. Luo ◽  
J. Li ◽  
Y. Wei ◽  
J. Lu ◽  
R. Dong
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cell ◽  
Normal Liver ◽  
Stellate Cells ◽  
Comprehensive Understanding ◽  
Fibrosis Progression ◽  
Liver Fibrogenesis ◽  
Fibrosis Regression ◽  
Space Of Disse

Hepatic stellate cells (HSCs) are located in the space of Disse, between liver sinusoidal endothelia cells (LSECs) and hepatocytes. They have surprised and excited hepatologists for their biological characteristics. Under physiological quiescent conditions, HSCs are the major vitamin A-storing cells of the liver, playing crucial roles in the liver development, regeneration, and tissue homeostasis. Upon injury-induced activation, HSCs convert to a pro-fibrotic state, producing the excessive extracellular matrix (ECM) and promoting angiogenesis in the liver fibrogenesis. Activated HSCs significantly contribute to liver fibrosis progression and inactivated HSCs are key to liver fibrosis regression. In this review, we summarize the comprehensive understanding of HSCs features, including their roles in normal liver and liver fibrosis in hopes of advancing the development of emerging diagnosis and treatment for hepatic fibrosis.

scholarly journals DNA Methylation Status in Cancer Disease: Modulations by Plant-Derived Natural Compounds and Dietary Interventions

Biomolecules ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. 289 ◽  
Author(s):  
Karin Jasek ◽  
Peter Kubatka ◽  
Marek Samec ◽  
Alena Liskova ◽  
Karel Smejkal ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Human Cancer ◽  
Rapid Development ◽  
Methylation Status ◽  
Dna Methyltransferases ◽  
Epigenetic Mechanism ◽  
Preclinical Research ◽  
Gene Expressions ◽  
Wide Range

The modulation of the activity of DNA methyltransferases (DNMTs) represents a crucial epigenetic mechanism affecting gene expressions or DNA repair mechanisms in the cells. Aberrant modifications in the function of DNMTs are a fundamental event and part of the pathogenesis of human cancer. Phytochemicals, which are biosynthesized in plants in the form of secondary metabolites, represent an important source of biomolecules with pleiotropic effects and thus provide a wide range of possible clinical applications. It is well documented that phytochemicals demonstrate significant anticancer properties, and in this regard, rapid development within preclinical research is encouraging. Phytochemicals affect several epigenetic molecular mechanisms, including DNA methylation patterns such as the hypermethylation of tumor-suppressor genes and the global hypomethylation of oncogenes, that are specific cellular signs of cancer development and progression. This review will focus on the latest achievements in using plant-derived compounds and plant-based diets targeting epigenetic regulators and modulators of gene transcription in preclinical and clinical research in order to generate novel anticancer drugs as sensitizers for conventional therapy or compounds suitable for the chemoprevention clinical setting in at-risk individuals. In conclusion, indisputable anticancer activities of dietary phytochemicals linked with proper regulation of DNA methylation status have been described. However, precisely designed and well-controlled clinical studies are needed to confirm their beneficial epigenetic effects after long-term consumption in humans.

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