The transcriptomic response of rat hepatic stellate cells to endotoxin: implications for hepatic inflammation and immune regulation
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE49980 | GEO | 2013/10/31
SECONDARY ACCESSION(S): PRJNA215744
REPOSITORIES: GEO
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Project description:Located in the perisinusoidal space of Disse, hepatic stellate cells (HSCs) communicate with all other liver cell types by physical association and / or by producing cytokines and chemokines. In liver disease and folllowing liver transplantation, elevated levels of endotoxin (bacterial lipopolysaccharide: LPS) stimulate HSCs to produce increased amounts of cytokines and chemokines. Transcriptomic analysis of cultured HSCs stimulated with LPS yields a survey of expression changes which potentially modulate the hepatic inflammatory and immune responses. In two independent experiments, rat HSCs were cultured with or without 10 ng/ml LPS for 1h and 24h, then harvested for microarray analysis (i.e., 8 samples). In the first of these experiments, cells also were also harvested after 3, 6 and 12 hours of LPS treatment, for a total of 11 samples.
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Project description:Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nano-sized extracellular vesicles (EVs) and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated upregulation of EV-related pathways in the liver pericentral zone, which was abrogated by the glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs upregulated the expression of EV-related genes such as RAB31 by enhancing histone-3-lysine-9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.
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Project description:The molecular determinants of a healthy human liver cell phenotype remain largely uncharacterized. In addition, the gene expression changes associated with activation of primary human hepatic stellate cells, a key event during fibrogenesis, remain poorly characterized. Here, we provide the transriptomic profile underpinning the healthy phenotype of human hepatocytes, liver sinusoidal endothelial cells (LSECs) and quiescent hepatic stellate cells (qHSCs) as well as activated HSCs (aHSCs) We assess the transcriptome for purified, non-cultured human hepatocytes, liver sinusoidal cells (LSECs) and quiescent hepatic stellate cells (qHSCs) as well as culture-activated HSCs (aHSCs). Hepatocytes (n=2 donors), LSECs (n=3), qHSCs (n=3) and in vitro activated HSCs (n=3; from the same donors as the qHSCs and LSECs) were used for this study.
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2016-03-02 | GSE68000 | GEO
Project description:Liver fibrosis is a reversible wound-healing response to liver injury and hepatic stellate cells (HSCs) are central cellular players that mediate hepatic fibrogenesis. However, the molecular mechanisms that govern this process remain unclear. Expression profiling was used to explore the potential impact of VDR signaling in TGF?1 and TGF?1+1,25(OH)2D3-treated primary rat HSCs. Notably, 1,25(OH)2D3 treatment attenuated the culture-induced activation of HSCs, such that the transcriptome of treated cells closely resembled that of freshly isolated quiescent cells (Figure 2A), and co-treatment of 1,25(OH)2D3 together with TGF? resulted in considerable repression of a large set of TGF? induced genes. We also demonstrated that in primary mouse HSCs, calcipotriol potently repressed fibrotic gene expression, suggesting that the anti-TGF? properties of VDR agonists are likely conserved across mammalian species. Total RNA from primary rat HSCs were isolated and treated 1,25(OH)2D3 (100nM) for 24 hours to determine how Vitamin D ligands can impact the activated stellate cell state.
2013-04-29 | E-GEOD-41579 | biostudies-arrayexpress
Project description:Liver fibrosis is a reversible wound-healing response to liver injury and hepatic stellate cells (HSCs) are central cellular players that mediate hepatic fibrogenesis. However, the molecular mechanisms that govern this process remain unclear. Here, we reveal a novel cistromic circuit in HSCs comprising the vitamin D receptor (VDR) and SMAD transcription factors that restrains the intensity of hepatic fibrogenesis. Ligand-activated VDR suppresses TGFβ1-induced pro-fibrotic gene expression in HSCs. Administration of a vitamin D analogue, calcipotriol, diminishes the fibrotic response in a mouse model of liver fibrosis, while VDR knockout mice spontaneous develop extensive hepatic fibrosis by age 6 months. Using ChIP-Seq, we find that the anti-fibrotic properties of VDR are due to crosstalk with SMAD, mediated by their co-occupancy of DNA-binding sites on pro-fibrotic genes. Specifically, SMAD binding potentiates local chromatin accessibility to enhance VDR recruitment at the same cis-regulatory elements, which reciprocally antagonizes the interaction between SMAD3 and chromatin and limits the assembly of transcriptional activation complexes at fibrotic genes, a process that is enhanced by the presence of VDR agonists. These results not only establish this coordinated VDR/SMAD cistromic circuit as a master regulator of hepatic fibrogenesis, but also support VDR as a potential drug target to ameliorate liver fibrosis. Identification of VDR, SMAD3 and H3 binding sites in human stellate LX2 cells that were pre-treated with calcipotriol (100nM) for 16 hrs (where calcipotriol treatment is indicated) followed by incubation of calcipotriol (100nM) or TGFβ1 (1ng/ml) for another 4 hours (where indicated).
2013-04-29 | E-GEOD-38103 | biostudies-arrayexpress
Project description:Background & Aims Parathyroid hormone receptor-1 (PTH1R) is a class B G protein-coupled receptor central to skeletal development, bone turnover, and calcium homeostasis. However, the role of PTH1R signaling in liver fibrosis is largely unknown. Here, the role of PTH1R signaling in the activation of hepatic stellate cells (HSCs) and hepatic fibrosis was examined. Approach & Results PTH1R was highly expressed in activated HSCs and fibrotic liver by using human liver specimens or carbon tetrachloride (CCl4)-treated or methionine and choline-deficient diet (MCD)-fed C57/BL6 mice. The mRNA level of hepatic PTH1R was positively correlated to α-smooth muscle actin (α-SMA) in patients with liver cirrhosis. Mice with HSCs-specific PTH1R deletion were protected from CCl4, MCD, or western diet plus low-dose CCl4-induced liver fibrosis. Conversely, parathyroid hormone (PTH) aggravated liver fibrosis in CCl4-treated mice. Mouse primary HSCs and LX2 cell lines were used for in vitro experiments. Molecular analyses by luciferase reporter assays and chromatin-immunoprecipitation assays in combination with mRNA sequencing in HSCs revealed that cAMP response element-binding protein-like 2 (Crebl2), a novel regulator in HSCs treated by PTH that interacted with Mothers against decapentaplegic homolog 3 (SMAD3) and increased the transcription of transforming growth factor β (TGFβ) in activating HSCs and collagen deposition. In agreement, HSCs-specific Crebl2 deletion ameliorated PTH-induced liver fibrosis in CCl4-treated mice. Conclusions In both mouse and human models, we found that PTH1R was highly expressed in activated HSCs and fibrotic liver. PTH1R signaling regulated collagen production in the HSCs via Crebl2/SMAD3/TGFβ regulatory circuits. Blockade of PTH1R signaling in HSCs might help mitigate the development of liver fibrosis.
2023-03-29 | GSE227902 | GEO