High levels of glucose promote the activation of hepatic stellate cells via the p38-mitogen-activated protein kinase signal pathway

Wu, Lingkang; Liu, Y C; Ma, Genshan; Shi, Liangliang; He, Xing

doi:10.4238/gmr.15038419

Cited by 14 publications

(13 citation statements)

References 14 publications

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“…Mechanistically, this has been shown to be due to CYP2E1/leptin/purinergic receptor X7-mediated phosphorylation of AKT. Finally, high glucose in culture media of HSCs has been shown to trigger activation via the p38-MAPK cascade and ROS [98,99]. The fact that activation of glycolysis and lactate accumulation is a prerequisite for HSC trans-differentiation was demonstrated by treatment with Hh inhibitor GDC-0449 (targets smoothened) and the glycolytic inhibitor curcumin [93,100,101].…”

Section: Central Carbon and Nitrogen Metabolismmentioning

confidence: 99%

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Khomich

Ivanov

Bartosch

2019

Cells

144

154

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Liver fibrosis is a regenerative process that occurs after injury. It is characterized by the deposition of connective tissue by specialized fibroblasts and concomitant proliferative responses. Chronic damage that stimulates fibrogenic processes in the long-term may result in the deposition of excess matrix tissue and impairment of liver functions. End-stage fibrosis is referred to as cirrhosis and predisposes strongly to the loss of liver functions (decompensation) and hepatocellular carcinoma. Liver fibrosis is a pathology common to a number of different chronic liver diseases, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis. The predominant cell type responsible for fibrogenesis is hepatic stellate cells (HSCs). In response to inflammatory stimuli or hepatocyte death, HSCs undergo trans-differentiation to myofibroblast-like cells. Recent evidence shows that metabolic alterations in HSCs are important for the trans-differentiation process and thus offer new possibilities for therapeutic interventions. The aim of this review is to summarize current knowledge of the metabolic changes that occur during HSC activation with a particular focus on the retinol and lipid metabolism, the central carbon metabolism, and associated redox or stress-related signaling pathways.Most of the progress that has been made in the identification of the molecular mechanisms underlying fibrosis is based on the use of in vitro model systems using tissue culture-adapted HSC lines, primary HSC preparations, and a number of in vivo models such as animals being fed high-fat/cholesterol or choline-deficient diets, animals that undergo bile duct ligation, treatment with ethanol, CCl 4 or other chemical agents, or transgenic animals [5]. Hepatic Stellate CellsThe cell type that is predominantly responsible for fibrotic processes is hepatic stellate cells (HSCs), a mesenchymal cell population that constitutes 5-10% of the total number of cells in the liver (Figure 1). HSCs are located in the perisinusoidal space (space of Disse) and are surrounded by hepatocytes and sinusoidal endothelial cells [6,7]. Their main functions are the secretion of laminin, proteoglycans, and type IV collagen to form basement membrane-like structures. Quiescent HSCs start to proliferate and undergo trans-differentiation into contractile myofibroblasts in response to paracrine stimulation by neighboring cell types, including Kupffer cells, hepatocytes, platelets, leukocytes, and sinusoidal endothelial cells. Kupffer cells can stimulate activation and proliferation of HSCs through the actions of cytokines, and in particular transforming growth factor β1 (TGFβ1), interleukin 1 (IL-1), tumor necrosis factor (TNF), reactive oxygen species (ROS) and lipid peroxides [6,8]. Hepatocytes are an important source of inflammatory lipid peroxides in liver diseases. Platelets release pro-fibrogenic growth factors such as platelet-derived growth factor (PDGF), TGFβ1, and epidermal growth factor (EGF). Neutrophils are an important source of RO...

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Section: Central Carbon and Nitrogen Metabolismmentioning

confidence: 99%

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Khomich

Ivanov

Bartosch

2019

Cells

144

154

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“…Bioinformatics screening indicated MAPK1 served as a target of miR-326. MAPK1, mitogen-activated protein kinase 1, belongs to MAP kinase family and is a key member of MAPK/ERK pathway [22, 23]. It widely participates in various pathological processes of cancer cells, including cell proliferation, migration, cell differentiation, cell survival and apoptosis [24].…”

Section: Introductionmentioning

confidence: 99%

The lncRNA TDRG1 promotes cell proliferation, migration and invasion by targeting miR-326 to regulate MAPK1 expression in cervical cancer

et al. 2019

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Background Recently, lncRNA-Testis developmental related gene 1 (TDRG1) was proved to be a key modulator in reproductive organ-related cancers. The biological role of TDRG1 in cervical cancer (CC) progression remains largely unknown. Method Real-time PCR (qRT-PCR) examined the expression level of TDRG1, microRNA (miR)-326 and MAPK1 mRNA. OS tissues and corresponding relative normal tissues, as well as CC cell lines and normal cell line Ect1/E6E7 were collected to determine the expression of TDRG1 in CC. MTT, colony formation, wound-healing, transwell and flow cytometer assay detected the influence of TDRG1 and miR-326 on CC cells growth, metastasis and apoptosis. Western blot examined proteins level. Bioinformatics, RNA pull-down assay, RNA immunoprecipitation and dual-luciferase reporter assays detected the molecular mechanism of TDRG1 in CC. Xenograft tumour model was established to determine the role of TDRG1 in vivo. Results The expression of TDRG1 was significantly increased in CC tissues and cell lines compared with normal tissue and normal cell line respectively and its expression was associated with clinicopathological characteristics of CC patients. Knockdown of TDRG1 inhibited the cell proliferation, migration and invasion in Hela and SIHA cells. Moreover, TDRG1 directly interacted with miR-326, and the inhibition effect on cell growth and metastasis induced by TDRG1 siRNA can be abrogated by miR-326 silencing by its inhibitor in Hela and SIHA cells. Further, MAPK1 was proved to be a direct target of miR-326, and its expression was negatively regulated by miR-326 while positively modulated by TDRG1. Conclusion TDRG1 acts as a competing endogenous lncRNA (ceRNA) to modulate MAPK1 by sponging miR-326 in CC, shedding new light on TDRG1-directed diagnostics and therapeutics in CC.

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“…Mitogen-activated protein kinase 1 ( MAPK1 ) belongs to the MAP kinase family. MAP kinase, also known as extracellular signal-regulated kinases (ERKs), could act as a binding point for numerous biochemical signals [ 19 , 20 ]. Besides, ERKs are also involved in a wide range of cellular processes, such as differentiation, proliferation, transcription development and regulation [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

MiR-143 inhibits endometrial cancer cell proliferation and metastasis by targetingMAPK1

et al. 2017

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Endometrial cancer (EC) is one of the most commonly diagnosed gynecologic malignancies in the world, with the morbidity rate of over 7%. The mechanism of the pathogenesis has not been specifically elucidated to date, which is imperative for EC treatment. The aim of our study was to investigate the target relationship between miR-143 and mitogen-activated protein kinase 1 (MAPK1) and explore the effect of miR-143 on the endometrial cancers (EC) cells through targeting MAPK1. We collected EC tissues and adjacent tissues, and transfected miR-143 mimics and MAPK1 siRNA into EC cells with lipofectamine. Reverse transcription-polymerase chain reaction (RT-PCR) and western blot were used to examine the expression of miR-143 and MAPK1 mRNA and the protein expression of MAPK1. Cell counting kit-8, wound healing assay, flow cytometry and transwell assay were applied to examining the alteration of the proliferation, migration, cell cycle and invasion ability of EC cells. We predicted the targeting gene of miR-143 through bioinformatics analysis. MiR-143 was found under-expressed in EC tissues and cells. Overexpression of miR-143 or knockdown of MAPK1 in human EC cell line HEC-1B inhibited the EC cell proliferation, migration and invasion and induced apoptosis. MAPK1 was verified to be a target gene of miR-143. MiR-143 overexpression could effectively inhibit mRNA and protein expression of MAPK1 in HEC-1B cells. Collectively, miR-143 might inhibit the proliferation, migration and invasion of EC cells, and promote the apoptosis of EC cells by suppressing MAPK1. These findings provided a view for new and potential therapeutic method for the clinical treatment of EC.

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High levels of glucose promote the activation of hepatic stellate cells via the p38-mitogen-activated protein kinase signal pathway

Cited by 14 publications

References 14 publications

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

Metabolic Hallmarks of Hepatic Stellate Cells in Liver Fibrosis

The lncRNA TDRG1 promotes cell proliferation, migration and invasion by targeting miR-326 to regulate MAPK1 expression in cervical cancer

MiR-143 inhibits endometrial cancer cell proliferation and metastasis by targetingMAPK1

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