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Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver

ABSTRACT: Gene Set Enrichment Analysis of PEDF knockout livers revealed induction of pathways associated with experimental and human HCC and a transcriptional profile characterized by Wnt/β-catenin activation Genome-wide expression analysis of liver tissue of wild type vs PEDF knockout animals fed high fat diet

ORGANISM(S): Mus musculus

PROVIDER: GSE63643 | GEO | 2015/03/30

SECONDARY ACCESSION(S): PRJNA268520

REPOSITORIES: GEO

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Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/β-catenin Signaling in the Liver

Project description:Gene Set Enrichment Analysis of PEDF knockout livers revealed induction of pathways associated with experimental and human HCC and a transcriptional profile characterized by Wnt/β-catenin activation Genome-wide expression analysis of liver tissue of wild type vs PEDF knockout animals fed high fat diet Total RNA was extracted from whole liver tissue

2015-03-30 | E-GEOD-63643 | biostudies-arrayexpress

Pigment Epithelium-Derived Factor (PEDF) Inhibits Wnt/<i>β</i>-catenin Signaling in the Liver.

Project description:Background & aimsPigment epithelium-derived factor (PEDF) is a secretory protein that inhibits multiple tumor types. PEDF inhibits the Wnt coreceptor, low-density lipoprotein receptor-related protein 6 (LRP6), in the eye, but whether the tumor-suppressive properties of PEDF occur in organs such as the liver is unknown.MethodsWnt-dependent regulation of PEDF was assessed in the absence and presence of the Wnt coreceptor LRP6. Whole genome expression analysis was performed on PEDF knockout (KO) and control livers (7 months). Interrogation of Wnt/β-catenin signaling was performed in whole livers and human hepatocellular carcinoma (HCC) cell lines after RNA interference of PEDF and restoration of a PEDF-derived peptide. Western diet feeding for 6 to 8 months was used to evaluate whether the absence of PEDF was permissive for HCC formation (n = 12/group).ResultsPEDF levels increased in response to canonical Wnt3a in an LRP6-dependent manner but were suppressed by noncanonical Wnt5a protein in an LRP6-independent manner. Gene set enrichment analysis (GSEA) of PEDF KO livers revealed induction of pathways associated with experimental and human HCC and a transcriptional profile characterized by Wnt/β-catenin activation. Enhanced Wnt/β-catenin signaling occurred in KO livers, and PEDF delivery in vivo reduced LRP6 activation. In human HCC cells, RNA interference of PEDF led to increased levels of activated LRP6 and β-catenin, and a PEDF 34-mer peptide decreased LRP6 activation and β-catenin signaling, and reduced Wnt target genes. PEDF KO mice fed a Western diet developed sporadic well-differentiated HCC. Human HCC specimens demonstrated decreased PEDF staining compared with hepatocytes.ConclusionsPEDF is an endogenous inhibitor of Wnt/β-catenin signaling in the liver.

| S-EPMC4604042 | biostudies-literature

Pigment epithelium-derived factor (PEDF) on gene expression of mouse empbryonic fibroblasts (MEF)

Project description:Exercise training has been reported to induce changes in cellular homeostasis in various tissues, but the exact mechanisms remain unclear. Our findings demonstrate that in a mouse model, muscle-derived PEDFs have the capacity to intricately regulate cellular function at distal sites after training. The aim of this study was to investigate the effects of PEDF on gene expression in cultured MEFs and to elucidate the complex mechanisms involved.

2024-06-05 | GSE241459 | GEO

Pigment Epithelium Derived Factor (PEDF) secreted from iPSC derived-RPE facilitates apoptotic causes cell death, not the differentiation, of iPSCs

Project description:We show that Retinal pigment epithelium (RPE) secreted-factor, pigment epithelium derived factor (PEDF) secreted/derived from primary or iPSC-derived retinal pigment epithelium (RPE)RPE, dramatically inhibitsed the cell growth of iPSCs. PEDF was detected abundantly in culture supernatant media of primary and iPSC-derived RPE. We examined the gene expression in primary RPE and iPS-derived RPE.

2013-01-03 | GSE43257 | GEO

Pigment Epithelium Derived Factor (PEDF) secreted from iPSC derived-RPE facilitates apoptotic causes cell death, not the differentiation, of iPSCs

2013-01-03 | E-GEOD-43257 | biostudies-arrayexpress

Gut-liver axis calibrates intestinal stem cell fitness via PEDF

Project description:The gut and liver are recognized to mutually communicate through the biliary tract, portal vein and systemic circulation, but it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy, transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, that restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/b-catenin signaling pathway. Further, we found that microbial danger signals occurring as a result of intestinal inflammation can be sensed by the liver to repress PEDF production via peroxisome proliferator-activated receptor-a (PPARa), liberating ISC proliferation to accelerate tissue repair in the gut. Finally, treatment of mice with fenofibrate, a clinical agent of PPARa agonist for hypolipidemia enhances the susceptibility of colitis via PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis via reciprocal interactions between the gut and liver.

2024-01-16 | GSE228829 | GEO

Pigment epithelium–derived factor promotes peritoneal dissemination of ovarian cancer through induction of immunosuppressive macrophages

Project description:Peritoneal dissemination of ovarian cancer (OC) correlates with poor prognosis, but the mechanisms underlying the escape of OC cells from the intraperitoneal immune system have remained unknown. We here identify pigment epithelium–derived factor (PEDF) as a regulator of OC cell dissemination, which functions through induction of CD206+ IL-10–producing macrophages. High PEDF gene expression was associated with poor prognosis in OC patients. Concentrations of PEDF in ascites and serum were significantly higher in OC patients than those with more benign tumors and correlated with early recurrence of OC patients, suggesting that PEDF might serve as a prognostic biomarker. Bromodomain and extraterminal (BET) inhibitors were found to reduce PEDF expression and limit both OC cell survival and CD206+ macrophage induction in the peritoneal cavity. Our results thus implicate PEDF as a driver of OC dissemination and identify a BET protein–PEDF–IL-10 axis as a promising therapeutic target for OC.

2022-04-25 | GSE201275 | GEO

Pigment epithelium-derived factor (PEDF) on gene expression of mouse empbryonic fibroblasts (MEF)

Project description:Pigment epithelium-derived factor (PEDF) on gene expression of mouse empbryonic fibroblasts (MEF)

| PRJNA1008192 | ENA

Degradation of Photoreceptor Outer Segments by the Retinal Pigment Epithelium Requires Pigment Epithelium-Derived Factor Receptor (PEDF-R).

Project description:PurposeTo examine the contribution of pigment epithelium-derived factor receptor (PEDF-R) to the phagocytosis process. Previously, we identified PEDF-R, the protein encoded by the PNPLA2 gene, as a phospholipase A2 in the retinal pigment epithelium (RPE). During phagocytosis, RPE cells ingest abundant phospholipids and protein in the form of photoreceptor outer segment (POS) tips, which are then hydrolyzed. The role of PEDF-R in RPE phagocytosis is not known.MethodsMice in which PNPLA2 was conditionally knocked out (cKO) in the RPE were generated. Mouse RPE/choroid explants were cultured. Human ARPE-19 cells were transfected with siPNPLA2 silencing duplexes. POSs were isolated from bovine retinas. The phospholipase A2 inhibitor bromoenol lactone was used. Transmission electron microscopy, immunofluorescence, lipid labeling, pulse-chase experiments, western blots, and free fatty acid and β-hydroxybutyrate assays were performed.ResultsThe RPE of the cKO mice accumulated lipids, as well as more abundant and larger rhodopsin particles, compared to littermate controls. Upon POS exposure, RPE explants from cKO mice released less β-hydroxybutyrate compared to controls. After POS ingestion during phagocytosis, rhodopsin degradation was stalled both in cells treated with bromoenol lactone and in PNPLA2-knocked-down cells relative to their corresponding controls. Phospholipase A2 inhibition lowered β-hydroxybutyrate release from phagocytic RPE cells. PNPLA2 knockdown also resulted in a decline in fatty acids and β-hydroxybutyrate release from phagocytic RPE cells.ConclusionsPEDF-R downregulation delayed POS digestion during phagocytosis. The findings imply that the efficiency of RPE phagocytosis depends on PEDF-R, thus identifying a novel contribution of this protein to POS degradation in the RPE.

| S-EPMC7900850 | biostudies-literature

Pigment epithelium-derived factor receptor (PEDF-R): a plasma membrane-linked phospholipase with PEDF binding affinity.

Project description:Pigment epithelium-derived factor (PEDF), a multifunctional protein, acts in retinal differentiation, survival and maintenance by interacting with high affinity receptors on the surface of target cells. We have recently identified PEDF-R, a new member of the patatin-like phospholipase domain-containing 2 (PNPLA2) family with characteristics of a PEDF receptor. The PEDF-R sequence reveals a patatin-like phospholipase domain toward its amino-end, and four transmembrane domains interrupted by two extracellular loops and three intracellular regions along its polypeptide sequence. This newly identified protein is present on the surface of retina and RPE cells, and has the expected transmembrane topology. It has specific and high binding affinity for PEDF, and exhibits a potent phospholipase A(2) activity that liberates fatty acids. Most importantly, PEDF binding stimulates the enzymatic phospholipase A(2) activity of PEDF-R. In summary, PEDF-R is a novel component of the retina that is a phospholipase-linked membrane protein with high affinity for PEDF. The results suggest a molecular pathway by which PEDF ligand/receptor interactions on the cell surface could generate a cellular signal. These conclusions enhance our understanding of the role of PEDF as a neurotrophic survival factor.

| S-EPMC3901638 | biostudies-literature

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