RNA-seq technique to identify key differentially expressed genes in hepatocytes of HFD-treated Lyve1-Cre;Heg1fl/fl mice.
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE315356 | GEO | 2026/06/18
REPOSITORIES: GEO
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Project description:Hereditary hemorrhagic telangiectasia (HHT, alias Rendu-Osler-Weber syndrome) is an autosomal dominant genetic disease that causes vascular malformations in multiple organs. Malformations and shunts in the liver are relevant for the long-term prognosis as they can lead to heart failure. Moreover, the role of ALK-1 in the hepatic vascular niche remains elusive. In this project, we aimed to establish a novel HHT model covering hepatic involvement by the disease and to investigate the role of ALK-1 in the hepatic vascular niche. We crossed Stab2-icre mice (MGI: 6741034) with Acvrl1-floxed mice (MGI: 4398901) to generate constitutive hepatic endothelial Acvrl1 knockout (Acvrl1-HEC-KO, alias Alk1-HEC-KO) mice. To dissect microvascular transcriptomic alterations, we performed RNA sequencing of freshly isolated hepatic endothelial cells from 3 months old mice. Transcriptomic analyses revealed an arterialization of hepatic vessels accompanied by loss of LYVE-1 and induction of Endomucin. The loss of endothelial Wnt2, Wnt9b, and Rspo3 led to a disruption of hepatic metabolic zonation with a dominance of periportal genes in Alk1-HEC-KO mice and HHT patients. Furthermore, we identified PRND (alias Doppel) and placenta growth factor (PlGF) as novel candidates of HHT pathogenesis in mice. ALK-1 controls hepatic metabolic zonation via Wnt signaling and suppresses PRND and PlGF that represent novel candidates in HHT pathogenesis.
2023-04-06 | GSE184747 | GEO
Project description:Hereditary hemorrhagic telangiectasia (HHT, alias Rendu-Osler-Weber syndrome) is an autosomal dominant genetic disease that causes vascular malformations in multiple organs. Malformations and shunts in the liver are relevant for the long-term prognosis as they can lead to heart failure. Moreover, the role of ALK-1 in the hepatic vascular niche remains elusive. In this project, we aimed to establish a novel HHT model covering hepatic involvement by the disease and to investigate the role of ALK-1 in the hepatic vascular niche. We crossed Stab2-icre mice (MGI: 6741034) with Acvrl1-floxed mice (MGI: 4398901) to generate constitutive hepatic endothelial Acvrl1 knockout (Acvrl1-HEC-KO, alias Alk1-HEC-KO) mice. To dissect hepatic transcriptomic alterations, we performed RNA sequencing of freshly isolated whole liver cells from 3 months old mice. Transcriptomic analyses revealed an arterialization of hepatic vessels accompanied by loss of LYVE-1 and induction of Endomucin. The loss of endothelial Wnt2, Wnt9b, and Rspo3 led to a disruption of hepatic metabolic zonation with a dominance of periportal genes in Alk1-HEC-KO mice and HHT patients. Furthermore, we identified PRND (alias Doppel) and placenta growth factor (PlGF) as novel candidates of HHT pathogenesis in mice. ALK-1 controls hepatic metabolic zonation via Wnt signaling and suppresses PRND and PlGF that represent novel candidates in HHT pathogenesis.
2023-04-06 | GSE184746 | GEO
Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal hepatic function. Wnt signaling is a master regulator of spatial liver zonation. A perivenous-periportal Wnt activity gradient orchestrates metabolic zonation by activating genes in perivenous hepatocytes, while suppressing genes in their periportal counterparts. The understanding of liver gene zonation and zonation regulators in disease was limited. Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fat accumulation, inflammation, and fibrosis. Here, we investigated the perturbation of liver gene zonation in a mouse NASH model by combination of spatial transcriptomics, bulk RNAseq and in situ hybridization. Wnt target genes represented a major subset of genes showing altered spatial expression in the NASH liver. The altered Wnt target gene expression level and zonation spatial pattern were in line with the upregulation of Wnt regulators and the augmentation of Wnt signaling. Particularly, we found that the Wnt activator Rspo3 expression was restricted to the perivenous zone in control livers, whereas expanded to the periportal zone in NASH livers. AAV8-mediated RSPO3 overexpression in controls resulted in a zonation change, and further amplified the disturbed zonation of Wnt target genes in NASH, but had no impacts on steatosis, inflammation and fibrosis. In summary, our study demonstrated the alteration of Wnt signaling in a mouse NASH model, leading to perturbed liver zonation.
2024-08-01 | GSE248077 | GEO
Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/beta-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/beta-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/beta-catenin. The glucagon and Wnt/beta-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counter play with the Wnt/beta-catenin signaling pathway.
2018-03-01 | GSE110673 | GEO
Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/beta-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/beta-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/beta-catenin. The glucagon and Wnt/beta-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counter play with the Wnt/beta-catenin signaling pathway.
2018-03-01 | GSE110672 | GEO
Project description:Genome-wide association identified SLC16A13 as novel type 2 diabetes gene locus. The SLC16A13 gene encodes for SLC16A13/MCT13, member of the solute carrier 16 family of monocarboxylate transporters. This transporter family recently raised interest in metabolic research with the identification of SLC16A11 polymorphisms associated with type 2 diabetes; and human as well as mouse data suggest causal relationship between SLC16A11/MCT11 transporter dysfunction and type 2 diabetes development. In contrast, SLC16A13 biology and physiological function is not characterized at all. Here, we validate SLC16A13 as monocarboxylate transporter expressed at the plasma membrane and report the first Slc16a13 knockout mouse line. Deletion of Slc16a13 ameliorates metabolic disease in the context of diet-induced obesity. The improved metabolic phenotype is characterized by increased mitochondrial respiration in the liver, leading to reduced hepatic lipid accumulation and increased insulin sensitivity of Slc16a13 knockout mice. Mechanistically, we propose reduced intracellular lactate availability in Slc16a13 knockout hepatocytes, affecting hepatic energy metabolism by AMPK activation and increased oxidative phosphorylation, reducing hepatic lipid content and insulin resistance in obese mice. Together, these data suggest SLC16A13/MCT13 as potential novel target to treat fatty liver, insulin resistance and related metabolic disorders.
2021-06-24 | GSE152937 | GEO
Project description:The metabolic functions of the liver are organized spatially in a phenomenon known as zonation. This spatial organization of metabolic functions is linked to the differential exposure of central and portal hepatocytes to either systemic circulation or nutrient-rich blood afferent from the gastrointestinal tract, respectively. The mechanistic target of rapamycin complex 1 (mTORC1) is the central hub of a critical signaling pathway that links cellular metabolism to fluctuations in the levels of nutrients and insulin. To understand how these two signaling cues are integrated in the liver, we have generated mice with constitutive nutrient and insulin signaling to mTORC1 in hepatocytes (RragaGTP/fl; Tsc1fl/fl; Albumin-CreTg mice). Simultaneous activation of nutrient and hormone signaling to mTORC1 results in impaired establishment of the metabolic zonal identity of hepatocytes, a maturation process that takes place within the first weeks after birth. Mechanistically, a decrease in levels of the morphogenic pathway Wnt/β-catenin in hepatocytes and reduced expression of the Wnt2 ligand by liver endothelial cells after birth underlie this impaired wave of hepatocyte maturation. Lack of postnatal establishment of metabolic zonation of the liver is recapitulated in a model of constant supply of nutrients by total parenteral nutrition to neonatal pigs. Collectively, our work shows the critical role of hepatocyte sensing of fluctuations in nutrients and hormones after birth for triggering the latent metabolic zonation program.
2024-03-18 | PXD041439 | Pride
Project description:Knockout of Heart-of-glass (Heg) in liver endothelial cells alters the metabolic patterns of hepatocytes. To further investigate whether endothelial cells regulate hepatocyte function and gene expression patterns by secreting certain proteins or factors mediated by Heg1, we collected mice at postnatal days 3 (P3) and 42 (P42), isolated liver endothelial cells, and performed RNA-seq analysis to explore the interaction patterns between endothelial cells and hepatocytes.
2026-06-18 | GSE315829 | GEO
Project description:Metabolic zonation in the liver is broadly defined as spatiotemporal variability in the intra-hepatic distribution of nutrients. R-spondin3 (Rspo3) regulates metabolic features around hepatic central veins. Herein, we demonstrate that altered hepatic metabolic zonation due to Rspo3 contributes to maintaining systemic glucose metabolism and body composition via inter-organ communication mechanism. Hepatic Rspo3 induction in obesity improves obesity-associated features by restoring insulin sensitivity, reversing adipose tissue enlargement and reversing overstimulated adaptive thermogenesis. These remote effects partly consist of neuronal communication via the afferent vagus from the liver. In contrast, hepatic Rspo3 suppression exacerbates diabetes due to insulin resistance and develops fatty liver.
2024-12-06 | GSE282890 | GEO
Project description:Liver sinusoidal endothelial cells (LSEC) are highly specialized within the hepatic vascular niche, controlling liver function and disease pathogenesis by angiocrine signaling. Recently, we identified GATA4 as a major transcription factor controlling LSEC development and protecting against liver fibrosis. As the transcription factor c-Maf was strongly downregulated in Gata4-deficient LSEC, we hypothesized that c-Maf might be an important downstream effector of GATA4 in LSEC differentiation and liver fibrogenesis. Clec4g-iCre/Maf fl/fl mice (Maf-LSEC-KO) mice with LSEC-specific Maf deficiency were generated and liver tissue was analyzed by histology, immunofluorescence, and in situ-hybridization at the age of three months. LSECs were isolated for RNA-, ATAC-seq, and single-cell RNA-seq (scRNA-seq) analysis. The expression of MAF and its targets were analyzed in published human scRNA-seq data. Endothelial Maf deficiency resulted in perisinusoidal liver fibrosis without affecting metabolic liver zonation, accompanied by a switch from sinusoidal to continuous endothelial differentiation. Furthermore, endothelial Maf deficiency caused hepatic endothelial proliferation and expression of profibrotic angiocrine factors such as Pdgfb, Igfbp5, Sparcl-1, and Flrt2. scRNA-seq revealed replacement of zonated LSEC subpopulations by capillarized, proliferative, sprouting and secretory endothelial cell subset promoting liver fibrogenesis and angiogenesis. This fundamental dysregulation of LSEC gene expression and differentiation was caused by changes in chromatin accessibility and transcription factor network alterations at promoter and enhancer regions following loss of Maf. Notably, endothelial MAF expression was also significantly reduced in human liver cirrhosis patients. Hepatic endothelial c-Maf protects against metabolic dysfunction-associated steatohepatitis-like liver fibrosis and regulates endothelial differentiation and zonation by controlling chromatin opening. Notably, our findings may open up new avenues to develop angiotargeted strategies for hepatic disease prevention and liver repair.
2025-07-17 | GSE281716 | GEO