RXRα Modulates Hepatic Stellate Cell Activation and Liver Fibrosis by Targeting CaMKKβ-AMPKα Axis
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PROVIDER: PRJNA1162045 | ENA |
REPOSITORIES: ENA
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Project description:Hepatic stellate cells (HSCs) represent a dominant fibrogenic cell population in the liver, whose activation is a key event in the development and progression of hepatic fibrosis. We report here that retinoid X receptor-alpha (RXRα), a unique member of the nuclear receptor superfamily, is a critical modulator of HSC activation and liver fibrosis through its regulation of calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ)-mediated activation of AMP-activated protein kinase-alpha (AMPKα). K-80003, which binds RXRα by a unique mechanism, effectively inhibits the activation, proliferation and migration of HSCs and inhibits liver fibrosis in the CCl4 and AMLN animal models by AMPKα activation, which promotes mitophagy in HSCs. Mechanistically, K-80003 activation of AMPKα requires its induction of RXRα formation of condensates with CaMKKβ and AMPKα via a two-phase mechanism. The formation of RXRα condensates is mediated by the N-terminal intrinsically disorder region of RXRα and is dependent on its phosphorylation by CaMKKβ. Our results therefore unravel an important RXRα-CaMKKβ-AMPKα axis in the modulation of HSC activation through phase separation and identify K-80003 as a potent inhibitor of HSC activation and liver fibrosis by targeting the axis.
2025-09-14 | GSE277363 | GEO
Project description:Gene expression of mouse hepatic stellate cells was characterized under the following conditions: Quiescent (isolated from normal mouse liver) and reverted (isolated from mouse liver treated with 4 injections of carbontetrachloride followed by 45 day rest period) Affymetrix Mouse 1.0ST gene expression measurements were used to characterize the transcriptomic basis in quiescent hepatic stellate cells, isolated from normal liver, and reverted hepatic stellate cells, isolated from liver treated with 4 injections of CCl4 followed by a 45 day rest period. Gene expression of mouse hepatic stellate cells was characterized under the following conditions: A. Quiescent control hepatic stellate cells (n=4). B. Reverted hepatic stellate cells (n=4).
2014-05-05 | E-GEOD-38648 | biostudies-arrayexpress
Project description:Chronic activation of hepatic stellate cells leads to irreversible liver fibrosis, and durable treatment options for liver fibrosis remain suboptimal, creating a critical clinical need. Amniotic fluid (AF) reduces inflammation and promotes tissue remodeling and regeneration when applied to cutaneous wounds and in models thereof. However, no prior studies have explored the anti-fibrotic benefits of AF in liver disease. Data from this study indicate that AF can repress liver fibrosis by reducing hepatic stellate cell myofibroblast activation. Thus, these findings lay the foundation for early-phase clinical trials investigating cell-free AF as a therapeutic treatment for liver fibrosis and as a bridging therapy for liver transplantation
2025-07-14 | PXD060743 | Pride
Project description:The activation of hepatic stellate cells (HSC) plays a crucial role in non-alcoholic fatty liver disease (NAFLD), which could further develop to non-alcoholic steatohepatitis (NASH) and liver fibrosis/cirrhosis. Since cGMP-dependent protein kinase 1 (cGK1) deficient (cGK1-KO) mice displayed hepatic insulin resistance we hypothesized that cGK1 modulates HSC activation and its metabolic consequences. First, retinol storage and gene expression were studied in cGK1-KO mice. Second, we investigated the effects of cGK1-silencing on gene expression in the human stellate cell line LX2. Finally, cGK1 expression was investigated in human liver biopsies covering a wide range of liver fat content. Retinyl-ester level in the liver of cGK1-KO mice was lower compared to wild-type animals, which was associated with increased inflammatory gene expression. mRNA regulation in cGK1-silenced LX2 cells showed stronger stellate cell activation profile, altered matrix degradation and elevated chemokine level. On the other hand, activation of LX2 cells suppressed cGK1 expression, which was associated with human data, showing a negative correlation between cGK1 mRNA and liver fat content in liver biopsies. These results suggest that the lack of cGK1 could possibly lead to stellate cell activation, which elevates chemokine expression and inflammatory processes, which in turn disturbs hepatic insulin sensitivity.
2018-09-11 | GSE111988 | GEO
Project description:Gene expression of mouse hepatic stellate cells was characterized under the following conditions: Quiescent (isolated from normal mouse liver) and reverted (isolated from mouse liver treated with 4 injections of carbontetrachloride followed by 45 day rest period) Affymetrix Mouse 1.0ST gene expression measurements were used to characterize the transcriptomic basis in quiescent hepatic stellate cells, isolated from normal liver, and reverted hepatic stellate cells, isolated from liver treated with 4 injections of CCl4 followed by a 45 day rest period.
2014-05-05 | GSE38648 | GEO
Project description:cGMP-dependent protein kinase 1 (cGK1) modulates human hepatic stellate cell activation
| PRJNA438888 | ENA
Project description:We report the effect of TGFβ vs PDGF 2h treatment in hepatic stellate cells. We also report the effect of TGFβ treatment for 48h in human hepatic stellate cells.
2018-09-07 | GSE119606 | GEO
Project description:Retinoid X receptor alpha (RXRα) is a ligand-activated nuclear receptor involved in the regulation of retinoid metabolism. RXRα activation by agonist bexarotene can significantly induce hepatomegaly and promote liver regeneration after 70% partial hepatectomy (PHx) in wild type mice, while these effects were abolished in liver-specific RXRα-knockout mice. However, the underlying mechanisms remain unclear. Our findings reveal that RXRα activation promotes liver proliferation through transactivation of Cyclin D1. These data raise some key questions for understanding the manipulation of liver size and liver regeneration by RXRα agonists.
2026-02-03 | GSE317638 | GEO
Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.
2015-02-19 | E-GEOD-52253 | biostudies-arrayexpress
Project description:Effect of RXRα agonist bexarotene on gene expression in hepatocytes of hepatic RXRα knockout mice
| PRJNA1414579 | ENA