Browse
Submit Data
Databases
API
Help

Dataset Information

31 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Nuclear receptors FXR and SHP regulate protein N-glycan modifications in the liver.

ABSTRACT: Nuclear receptors farnesoid X receptor (FXR) and small heterodimer partner (SHP) are key regulators of metabolism. Here, we report a previously unknown function for the hepatic FXR-SHP axis in controlling protein N-linked glycosylation. Transcriptome analysis in liver-specific Fxr-Shp double knockout (LDKO) livers revealed induction of genes encoding enzymes in the N-glycosylation pathway, including Mgat5, Fut8, St3gal6, and St6gal1 FXR activation suppressed Mgat5, while Shp deletion induced St3gal6 and St6gal1 Increased percentages of core-fucosylated and triantennary glycan moieties were seen in LDKO livers, and proteins with the "hyperglycoforms" preferentially localized to exosomes and lysosomes. This up-regulation of N-glycosylation machinery was specific to the Golgi apparatus and not the endoplasmic reticulum. The increased glycan complexity in the LDKO correlated well with dilated unstacked Golgi ribbons and alterations in the secretion of albumin, cholesterol, and triglycerides. Our findings demonstrate a role for the FXR-SHP axis in maintaining glycoprotein diversity in the liver.

SUBMITTER: Mathur B

PROVIDER: S-EPMC8059921 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Nutrient-sensing nuclear receptors PPARα and FXR control liver energy balance.

Project description:The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state. We have also recently reported that these receptors have mutually antagonistic impacts on autophagy, which is induced by PPARα but suppressed by FXR. Secretion of multiple blood proteins is a major drain on liver energy and nutrient resources, and we present preliminary evidence that the liver secretome may be directly suppressed by PPARα, but induced by FXR. Finally, previous studies demonstrated a striking deficiency in bile acid levels in malnourished mice that is consistent with results in malnourished children. We present evidence that hepatic targets of PPARα and FXR are dysregulated in chronic undernutrition. We conclude that PPARα and FXR function coordinately to integrate liver energy balance.

| S-EPMC5373864 | biostudies-literature

Gene expression analysis of FXR null, SHP null, and double FXR/SHP null mice

Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.

2010-12-10 | E-GEOD-20599 | biostudies-arrayexpress

Genome wide transcriptomics analyses of livers reveal induction of N-glycosylation upon loss of nuclear receptors FXR and SHP

Project description:We performed high-throughput RNA-sequencing on livers from hepatocyte specific Fxr-/- Shp-/- double knockout mice, and identified upregulation of N-glycan protein modification machinery. This correlated positively with Golgi structural defects and alterations in the hepatic secretome. This study identifies a new role for hepatic FXR-SHP axis in Golgi dynamics and N-glycosylation, apart from its traditional function in nutrient metabolism.

2021-03-09 | GSE164447 | GEO

Gene expression analysis of FXR null, SHP null, and double FXR/SHP null mice

2010-12-10 | GSE20599 | GEO

Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR.

Project description:Nuclear hormone receptors (NHRs) are transcription factors that work in concert with co-activators and co-repressors to regulate gene expression. Some examples of ligands for NHRs include endogenous compounds such as bile acids, retinoids, steroid hormones, thyroid hormone, and vitamin D. This review describes the evolution of liver X receptors ? and ? (NR1H3 and 1H2, respectively), farnesoid X receptor (NR1H4), vitamin D receptor (NR1I1), pregnane X receptor (NR1I2), and constitutive androstane receptor (NR1I3). These NHRs participate in complex, overlapping transcriptional regulation networks involving cholesterol homeostasis and energy metabolism. Some of these receptors, particularly PXR and CAR, are promiscuous with respect to the structurally wide range of ligands that act as agonists. A combination of functional and computational analyses has shed light on the evolutionary changes of NR1H and NR1I receptors across vertebrates, and how these receptors may have diverged from ancestral receptors that first appeared in invertebrates.

| S-EPMC3033471 | biostudies-literature

Probiotic <i>Pediococcus pentosaceus</i> Li05 Improves Cholestasis through the FXR-SHP and FXR-FGF15 Pathways.

Project description:Primary sclerosing cholangitis (PSC), a rare chronic cholestatic liver disease, is characterized by intrahepatic or extrahepatic strictures accompanied by biliary fibrosis. So far, there are no effective therapies to slow down the progression of this disease. Farnesoid X receptors (FXRs) are ligand-activated transcription factors involved in the control of bile acid (BA) synthesis and enterohepatic circulation. Therefore, targeting FXRs holds promise as a potential approach for treating PSC. Pediococcus pentosaceus Li05 is a probiotic that was isolated from healthy volunteers and has previously been shown to have an anti-inflammatory effect in DSS-induced colitis. In this study, we established a 3,5-diethoxycarbonyl-1,4-Dihydrocollidine (DDC)-induced cholestasis mouse model and investigated the effects of Pediococcus pentosaceus Li05 on PSC. Our findings revealed that administration of Li05 significantly attenuated liver damage, hepatic inflammation, and fibrosis, as well as bile duct hyperplasia. Li05 activated the hepatic FXR-SHP and ileal FXR-FGF15 signaling pathways to decrease the expression of Cyp7a1. In addition, the Li05-modulated gut microbiota structure especially improved the abundance of 7α-dehydroxylation bacteria like Eubacterium. The intervention of Li05 also improved the intestinal barrier and reduced bacterial endotoxin translocation. Based on these findings, Li05 shows promise for future application as a therapeutic strategy for cholestasis.

| S-EPMC10708340 | biostudies-literature

Structural insights into the heterodimeric complex of the nuclear receptors FXR and RXR.

Project description:Farnesoid X receptor (FXR) is a member of the family of ligand-activated nuclear receptors. FXR plays critical roles in maintaining many metabolic pathways, including bile acid regulation and glucose and lipid homeostasis, and forms a heterodimeric complex with the retinoid X receptor (RXR). Despite the important roles of the FXR/RXR heterodimerization in human physiology, the molecular basis underlying the FXR/RXR interaction is still uncertain in the absence of a complex structure. Here, we report the heterodimeric structure of FXR and RXR in the presence of an FXR agonist (WAY-362450), RXR agonist (9-cis-retinoic acid), and a peptide derived from a steroid receptor coactivator (SRC2), revealing both unique and conserved modes for FXR heterodimerization. We found that the dimerization with RXR induced allosteric conformational changes on the coactivator-binding site of FXR. These changes enhanced the transcriptional activity of FXR by promoting the coactivator binding, thus suggesting a structural basis for the functional permissiveness of the FXR/RXR heterodimer complex. Furthermore, sequence analyses together with functional mutagenesis studies indicated that the helix H10 largely responsible for the dimerization is highly conserved and also critical for the FXR transcriptional activity. Our findings highlight the important roles of RXR heterodimerization in the nuclear receptor signaling, providing a potential framework to develop pharmaceutical agents in treating FXR/RXR-related diseases.

| S-EPMC6093246 | biostudies-literature

Defective FXR-SHP Regulation in Obesity Aberrantly Increases <i>miR-802</i> Expression, Promoting Insulin Resistance and Fatty Liver.

Project description:Aberrantly elevated expression in obesity of microRNAs (miRNAs), including the miRNA miR-802, contributes to obesity-associated metabolic complications, but the mechanisms underlying the elevated expression are unclear. Farnesoid X receptor (FXR), a key regulator of hepatic energy metabolism, has potential for treatment of obesity-related diseases. We examined whether a nuclear receptor cascade involving FXR and FXR-induced small heterodimer partner (SHP) regulates expression of miR-802 to maintain glucose and lipid homeostasis. Hepatic miR-802 levels are increased in FXR-knockout (KO) or SHP-KO mice and are decreased by activation of FXR in a SHP-dependent manner. Mechanistically, transactivation of miR-802 by aromatic hydrocarbon receptor (AHR) is inhibited by SHP. In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802. In patients with nonalcoholic fatty liver disease (NAFLD) and in obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the miR-802 promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of miR-802 by FXR-SHP is defective in obesity, resulting in increased miR-802 levels, insulin resistance, and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.

| S-EPMC7897352 | biostudies-literature

Pioneer factor Foxa2 enables ligand-dependent activation of type II nuclear receptors FXR and LXRα.

Project description:ObjectiveType II nuclear hormone receptors, including farnesoid X receptors (FXR), liver X receptors (LXR), and peroxisome proliferator-activated receptors (PPAR), which serve as drug targets for metabolic diseases, are permanently positioned in the nucleus and thought to be bound to DNA regardless of the ligand status. However, recent genome-wide location analysis showed that LXRα and PPARα binding in the liver is largely ligand-dependent. We hypothesized that pioneer factor Foxa2 evicts nucleosomes to enable ligand-dependent binding of type II nuclear receptors and performed genome-wide studies to test this hypothesis.MethodsATAC-Seq was used to profile chromatin accessibility; ChIP-Seq was performed to assess transcription factors (Foxa2, FXR, LXRα, and PPARα) binding; and RNA-Seq analysis determined differentially expressed genes in wildtype and Foxa2 mutants treated with a ligand (GW4064 for FXR, GW3965, and T09 for LXRα).ResultsWe reveal that chromatin accessibility, FXR binding, LXRα occupancy, and ligand-responsive activation of gene expression by FXR and LXRα require Foxa2. Unexpectedly, Foxa2 occupancy is drastically increased when either receptor, FXR or LXRα, is bound by an agonist. In addition, co-immunoprecipitation experiments demonstrate that Foxa2 interacts with either receptor in a ligand-dependent manner, suggesting that Foxa2 and the receptor, bind DNA as an interdependent complex during ligand activation. Furthermore, PPARα binding is induced in Foxa2 mutants treated with FXR and LXR ligands, leading to the activation of PPARα targets.ConclusionsOur model requires pioneering activity for ligand activation that challenges the existing ligand-independent binding mechanism. We also demonstrate that Foxa2 is required to achieve activation of the proper receptor - one that binds the added ligand - by repressing the activity of a competing receptor.

| S-EPMC8350412 | biostudies-literature

FXR and liver carcinogenesis.

Project description:Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer.

| S-EPMC4571316 | biostudies-other

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data