β2-adrenergic receptor promotes liver regeneration partially through crosstalk with c-met.
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ABSTRACT:
SUBMITTER: Tao X
PROVIDER: S-EPMC9237079 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Cardiac hypertrophy is a context-dependent phenomenon wherein a myriad of biochemical and biomechanical factors regulate myocardial growth through a complex large-scale signaling network. Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy signaling as a whole network and how this network acts in a context-dependent manner. Here, we developed a systematic approach, CLASSED (Context-specific Logic-bASed Signaling nEtwork Development), to revise a large-scale signaling model based on context-specific data and identify main reactions and new crosstalks regulating context-specific response. CLASSED involves four sequential stages with an automated validation module as a core which builds a logic-based ODE model from the interaction graph and outputs the model validation percent. The context-specific model is developed by estimation of default parameters, classified qualitative validation, hybrid Morris-Sobol global sensitivity analysis, and discovery of missing context-dependent crosstalks. Applying this pipeline to our prior-knowledge hypertrophy network with context-specific data revealed key signaling reactions which distinctly regulate cell response to isoproterenol, phenylephrine, angiotensin II and stretch. Furthermore, with CLASSED we developed a context-specific model of β-adrenergic cardiac hypertrophy. The model predicted new crosstalks between calcium/calmodulin-dependent pathways and upstream signaling of Ras in the ISO-specific context. Experiments in cardiomyocytes validated the model's predictions on the role of CaMKII-Gβγ and CaN-Gβγ interactions in mediating hypertrophic signals in ISO-specific context and revealed a difference in the phosphorylation magnitude and translocation of ERK1/2 between cardiac myocytes and fibroblasts. CLASSED is a systematic approach for developing context-specific large-scale signaling networks, yielding insights into new-found crosstalks in β-adrenergic cardiac hypertrophy.
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Project description:T-cell factor 7-like 2 (TCF7L2) is an important transcription factor of Wnt/?-catenin signaling, which has critical roles in ?-cell survival and regeneration. In preliminary screening assay, we found geniposide, a naturally occurring compound, was able to increase TCF7L2 mRNA level in Min6 cells. Here we aimed to investigate the role of geniposide in ?-cell and underlying mechanism involved. Geniposide was found to promote ?-cell survival by increasing ?-cell proliferation and decreasing ?-cell apoptosis in cultured mouse islets after challenge with diabetic stimuli. Geniposide protected ?-cell through activating Wnt signaling, enhanced expressions of TCF7L2 and GLP-1R, activated AKT, inhibited GSK3? activity, and promoted ?-catenin nuclear translocation. The protective effect of geniposide was remarkably suppressed by siRNAs against ?-catenin, or by ICG001 (?-catenin/TCF-mediated transcription inhibitor). Moreover, geniposide promoted ?-cell regeneration in vivo to normalize blood glucose in high-fat diet and db/db mice. Increased ?-cell proliferation was observed in pancreatic sections of geniposide-treated diabetic mice. Most importantly, geniposide triggered small islet-like cell clusters formation as a result of ?-cell neogenesis from ductal epithelium, which was well correlated with the increase in TCF7L2 expression. In exocrine cells isolated from mouse pancreas, geniposide could induce duct cell differentiation through upregulating TCF7L2 expression and activating JAK2/STAT3 pathway. Taken together, we identified a novel role of geniposide in promoting ?-cell survival and regeneration by mechanisms involving the activation of ?-catenin/TCF7L2 signaling. Our finding highlights the potential value of geniposide as a possible treatment for type 2 diabetes.
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Project description:Two major functions of the epigenome are to regulate gene expression and to suppress transposons. It is unclear how these functions are balanced during physiological challenges requiring tissue regeneration, where exquisite coordination of gene expression is essential. Transcriptomic analysis of seven time points following partial hepatectomy identified the epigenetic regulator UHRF1, which is essential for DNA methylation, as dynamically expressed during liver regeneration in mice. UHRF1 deletion in hepatocytes (Uhrf1HepKO) caused genome-wide DNA hypomethylation but, surprisingly, had no measurable effect on gene or transposon expression or liver homeostasis. Partial hepatectomy of Uhrf1HepKO livers resulted in early and sustained activation of proregenerative genes and enhanced liver regeneration. This was attributed to redistribution of H3K27me3 from promoters to transposons, effectively silencing them and, consequently, alleviating repression of liver regeneration genes, priming them for expression in Uhrf1HepKO livers. Thus, epigenetic compensation safeguards the genome against transposon activation, indirectly affecting gene regulation.
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Project description:Despite the diverse etiologies of drug-induced liver injury (DILI), innate immunity activation is a common feature involved in DILI progression. However, the involvement of innate immunity regulation in inflammation resolution and liver regeneration in DILI remains obscure. Herein, we identified the chemokine CCL5 as a central mediator of innate immunity regulation in the pathogenesis of DILI. First, we showed that serum and hepatic CCL5 levels are elevated in both DILI patients and an APAP-induced liver injury (AILI) mouse model. Interestingly, both nonparenchymal cells and stressed hepatocytes are cell sources of CCL5 induction in response to liver injury. Functional experiments showed that CCL5 deficiency has no effect on the early phase of AILI but promotes liver repair in the late phase mainly by promoting inflammation resolution and liver regeneration, which are associated with an increased number of hepatic M2 macrophages. Mechanistically, CCL5 can directly activate M1 polarization and impede M2 polarization through the CCR1- and CCR5-mediated activation of the MAPK and NF-κB pathways. We then showed that CCL5 inhibition mediated by either a CCL5-neutralizing antibody or the antagonist Met-CCL5 can greatly alleviate liver injury and improve survival in an AILI mouse model. Our data demonstrate CCL5 induction during DILI, identify CCL5 as a novel innate immunity regulator in macrophage polarization, and suggest that CCL5 blockage is a promising therapeutic strategy for the treatment of DILI.
| S-EPMC7331700 | biostudies-literature
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta-adrenergic receptor (β-AR) signaling on the activity of nutrient-sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high-fat diet (HFD), a high-fat/high-sugar Western diet (WD), a high-sugar diet with mixed carbohydrates (HCD), or a high-sucrose diet (HSD). After 6 week on diets, mice were treated with isoproterenol (ISO) and the activity of liver mTOR complex 1 (mTORC1)-related signaling analyzed by immunoblotting and correlated with tissue triglyceride and glycogen contents. ISO-stimulated AKT- and ERK-mediated activation of mTORC1 in STD-fed mice. Consumption of all four high-calorie diets exacerbated downstream activation of ribosomal protein S6 kinase beta-1 (S6K1) in response to ISO. S6K1 activity was greater with the fat-enriched HFD and WD and correlated with the presence of metabolic syndrome and a stronger activation of AKT and ERK1/2 pathways. Fat-enriched diets also increased triglyceride accumulation and inhibited glycogen mobilization under β-AR stimulation. In conclusion, crosstalk between β-AR and insulin signaling may contribute to HFD-induced hepatic steatosis through ERK1/2- and AKT-mediated hyperactivation of the mTORC1/S6K1 axis. The findings provide further rationale for the development of therapies aimed at targeting augmented β-AR signaling in the pathogenesis of NAFLD.
| S-EPMC8261682 | biostudies-literature
Project description:?-adrenergic receptors (?-ARs) modulate cardiotoxicity/cardioprotection through crosstalk with multiple signaling pathways. We have previously shown that ?2-ARs are cardioprotective during exposure to oxidative stress induced by doxorubicin (DOX). DOX cardiotoxicity is mediated in part through a Ca(2+)-dependent opening of the mitochondrial permeability transition (MPT), however the signals linking a cell surface receptor like the ?2-AR to regulators of mitochondrial function are not clear. The objective of this study was to assess mechanisms of crosstalk between ?2-ARs and mitochondrial cell death pathways. DOX administered to WT mice resulted in no acute mortality, however 85% of ?2-/- mice died within 30 min. Several pro- and anti-survival pathways were altered. The pro-survival kinase, ?PKC, was decreased by 64% in ?2-/- after DOX vs WT (p<0.01); the ?PKC activator ??RACK partially rescued these mice (47% reduction in mortality). Activity of the pro-survival kinase Akt decreased by 76% in ?2-/- after DOX vs WT (p<0.01). The ?1-antagonist prazosin restored Akt activity to normal and also partially reversed the mortality (45%). Deletion of the ?2-AR increased rate of Ca(2+) release by 75% and peak [Ca(2+)](i) by 20% respectively in isolated cardiomyocytes; the Ca(2+) channel blocker verapamil also partially rescued the ?2-/- (26%). Mitochondrial architecture was disrupted and complex I and II activities decreased by 40.9% and 34.6% respectively after DOX only in ?2-/-. The MPT blocker cyclosporine reduced DOX mortality by 41% and prazosin plus cyclosporine acted synergistically to decrease mortality by 85%. ?2-ARs activate pro-survival kinases and attenuate mitochondrial dysfunction during oxidative stress; absence of ?2-ARs enhances cardiotoxicity via negative regulation of survival kinases and enhancement of intracellular Ca(2+), thus predisposing the mitochondria to opening of the MPT.
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Project description:A unique feature of the liver is its high regenerative capacity, which is essential to maintain liver homeostasis. However, key regulators of liver regeneration (LR) remain ill-defined. Here, we identify hepatic miR-182-5p as a key regulator of LR. Suppressing miR-182-5p, whose expression is significantly induced in the liver of mice post two-thirds partial hepatectomy (PH), abrogates PH-induced LR in mice. In contrast, liver-specific overexpression of miR-182-5p promotes LR in mice with PH. Overexpression of miR-182-5p failed to promote proliferation in hepatocytes, but stimulates proliferation when hepatocytes are cocultured with stellate cells. Mechanistically, miR-182-5p stimulates Cyp7a1-mediated cholic acid production in hepatocytes, which promotes hedgehog (Hh) ligand production in stellate cells, leading to the activation of Hh signaling in hepatocytes and consequent cell proliferation. Collectively, our study identified miR-182-5p as a critical regulator of LR and uncovers a Cyp7a1/cholic acid-dependent mechanism by which hepatocytes crosstalk to stellate cells to facilitate LR.
2022-08-10 | GSE206451 | GEO
Project description:The β2 adrenergic receptor (β2AR) signals through both Gs and Gi in cardiac myocytes, and the Gi pathway counteracts the Gs pathway. However, Gi coupling is much less efficient than Gs coupling in most cell-based and biochemical assays, making it difficult to study β2AR-Gi interactions. Here we investigate the role of phospholipid composition on Gs and Gi coupling. While negatively charged phospholipids are known to enhance agonist affinity and stabilize an active state of the β2AR, we find that they impair coupling to Gi3 and facilitate coupling to Gs. Positively charged Ca2+ and Mg2+, known to interact with the negative charge on phospholipids, facilitates Gi3 coupling. Mutational analysis suggests that Ca2+ coordinates an interaction between phospholipid and the negatively charged EDGE motif on the amino terminal helix of Gi3. Taken together, our observations suggest that local membrane charge modulates the interaction between β2AR and competing G protein subtypes.
| S-EPMC6527575 | biostudies-literature
Project description:IntroductionTransforming growth factor beta (TGF-β) has a dual role during tumor progression, initially as a suppressor and then as a promoter. Epithelial TGF-β signaling regulates fibroblast recruitment and activation. Concurrently, TGF-β signaling in stromal fibroblasts suppresses tumorigenesis in adjacent epithelia, while its ablation potentiates tumor formation. Much is known about the contribution of TGF-β signaling to tumorigenesis, yet the role of TGF-β in epithelial-stromal migration during tumor progression is poorly understood. We hypothesize that TGF-β is a critical regulator of tumor-stromal interactions that promote mammary tumor cell migration and invasion.MethodsFluorescently labeled murine mammary carcinoma cells, isolated from either MMTV-PyVmT transforming growth factor-beta receptor II knockout (TβRII KO) or TβRIIfl/fl control mice, were combined with mammary fibroblasts and xenografted onto the chicken embryo chorioallantoic membrane. These combinatorial xenografts were used as a model to study epithelial-stromal crosstalk. Intravital imaging of migration was monitored ex ovo, and metastasis was investigated in ovo. Epithelial RNA from in ovo tumors was isolated by laser capture microdissection and analyzed to identify gene expression changes in response to TGF-β signaling loss.ResultsIntravital microscopy of xenografts revealed that mammary fibroblasts promoted two migratory phenotypes dependent on epithelial TGF-β signaling: single cell/strand migration or collective migration. At epithelial-stromal boundaries, single cell/strand migration of TβRIIfl/fl carcinoma cells was characterized by expression of α-smooth muscle actin and vimentin, while collective migration of TβRII KO carcinoma cells was identified by E-cadherin+/p120+/β-catenin+ clusters. TβRII KO tumors also exhibited a twofold greater metastasis than TβRIIfl/fl tumors, attributed to enhanced extravasation ability. In TβRII KO tumor epithelium compared with TβRIIfl/fl epithelium, Igfbp4 and Tspan13 expression was upregulated while Col1α2, Bmp7, Gng11, Vcan, Tmeff1, and Dsc2 expression was downregulated. Immunoblotting and quantitative PCR analyses on cultured cells validated these targets and correlated Tmeff1 expression with disease progression of TGF-β-insensitive mammary cancer.ConclusionFibroblast-stimulated carcinoma cells utilize TGF-β signaling to drive single cell/strand migration but migrate collectively in the absence of TGF-β signaling. These migration patterns involve the signaling regulation of several epithelial-to-mesenchymal transition pathways. Our findings concerning TGF-β signaling in epithelial-stromal interactions are important in identifying migratory mechanisms that can be targeted as recourse for breast cancer treatment.
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Project description:G protein-coupled receptors (GPCRs) are the largest class of human membrane proteins that bind extracellular ligands at their orthosteric binding pocket to transmit signals to the cell interior. Ligand binding evokes conformational changes in GPCRs that trigger the binding of intracellular interaction partners (G proteins, G protein kinases, and arrestins), which initiate diverse cellular responses. It has become increasingly evident that the preference of a GPCR for a certain intracellular interaction partner is modulated by a diverse range of factors, e.g., ligands or lipids embedding the transmembrane receptor. Here, by means of molecular dynamics simulations of the β2-adrenergic receptor and β-arrestin2, we study how membrane lipids and receptor phosphorylation regulate GPCR-arrestin complex conformation and dynamics. We find that phosphorylation drives the receptor's intracellular loop 3 (ICL3) away from a native negatively charged membrane surface to interact with arrestin. If the receptor is embedded in a neutral membrane, the phosphorylated ICL3 attaches to the membrane surface, which widely opens the receptor core. This opening, which is similar to the opening in the G protein-bound state, weakens the binding of arrestin. The loss of binding specificity is manifested by shallower arrestin insertion into the receptor core and higher dynamics of the receptor-arrestin complex. Our results show that receptor phosphorylation and the local membrane composition cooperatively fine-tune GPCR-mediated signal transduction. Moreover, the results suggest that deeper understanding of complex GPCR regulation mechanisms is necessary to discover novel pathways of pharmacological intervention.
| S-EPMC8733679 | biostudies-literature