Cytosol-nucleus traffic and colocalization with FXR of conjugated bile acids in rat hepatocytes

2008 ◽  
Vol 295 (1) ◽  
pp. G54-G62 ◽  
Author(s):  
Maria J. Monte ◽  
Ruben Rosales ◽  
Rocio I. R. Macias ◽  
Valeria Iannota ◽  
Almudena Martinez-Fernandez ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Bile Acids ◽  
Nuclear Receptors ◽  
Rat Hepatocytes ◽  
Nuclear Volume ◽  
Farnesoid X Receptor ◽  
Nuclear Accumulation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Rat Liver Cells

Bile acids (BAs) are natural ligands of nuclear receptors, in particular farnesoid X receptor (FXR). Whether, in addition to protein-mediated cytosolic-nuclear BA translocation, other mechanisms are involved in the access of BAs to nuclear FXR was investigated. When rat hepatocytes were incubated with radiolabeled taurocholic acid, taurodeoxycholic acid, taurochenodeoxycholic acid, and tauroursodeoxycholic acid, their nuclear accumulation was proportional to their intracellular levels. With the use of flow cytometry analysis, the accumulation by nuclei isolated from rat liver cells was found to differ for several fluorescent compounds of similar molecular weight and different charge, including fluorescein-tagged BAs [cholylglycyl amidofluorescein (CGamF), ursodeoxycholylglycyl amidofluorescein, or chenodeoxycholylglycyl amidofluorescein]. When we varied nuclear volume by incubation with different sucrose concentrations, a similar relationship between nuclear volume and content of FITC and 4-kDa FITC-dextran was found. In contrast, this relationship was markedly lower for CGamF. Confocal microscopy studies revealed that fluorescein-tagged BAs, but also FITC or 10-kDa FITC-dextran were found in the nuclear envelope and concentrated in regions where DNA was less densely packed. In contrast to the cytosolic subcellular localization of peroxisome proliferator-activated receptor-α, FXR and nucleolin (a marker of transcriptional active chromatin) were also localized by immunoreactivity in these intranuclear regions. In conclusion, although intranuclear levels of small organic molecules including conjugated BAs depend on their concentrations in the extranuclear space, the existence of certain molecular selectivity (not strictly dependent on molecular weight or charge) suggests that, in addition to simple diffusional exchange, other mechanisms may be also involved in determining their overall nuclear content in regions where these compounds coincide and may interact with nuclear receptors such as FXR.

Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α

2017 ◽  
Vol 35 (3) ◽  
pp. 203-209 ◽  
Author(s):  
Kang Ho Kim ◽  
David D. Moore
Keyword(s):  
Energy Balance ◽  
Nuclear Receptors ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Post Translational Modifications ◽  
Fed State ◽  
Fasted State ◽  
Opposing Effects ◽  
Metabolic Output

Background: The liver undergoes major changes in substrate utilization and metabolic output over the daily feeding and fasting cycle. These changes occur acutely in response to hormones such as insulin and glucagon, with rapid changes in signaling pathways mediated by protein phosphorylation and other post-translational modifications. They are also reflected in chronic alterations in gene expression in response to nutrient-sensitive transcription factors. Among these, the nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator activated receptor α (PPARα) provide an intriguing, coordinated response to maintain energy balance in the liver. FXR is activated in the fed state by bile acids returning to the liver, while PPARα is activated in the fasted state in response to the free fatty acids produced by adipocyte lipolysis or possibly other signals. Key Messages: Previous studies indicate that FXR and PPARα have opposing effects on each other's primary targets in key metabolic pathways including gluconeogenesis. Our more recent work shows that these 2 nuclear receptors coordinately regulate autophagy: FXR suppresses this pathway of nutrient and energy recovery, while PPARα activates it. Another recent study indicates that FXR activates the complement and coagulation pathway, while earlier studies identify this as a negative target of PPARα. Since secretion is a very energy- and nutrient-intensive process for hepatocytes, it is possible that FXR licenses it in the nutrient-rich fed state, while PPARα represses it to spare resources in the fasted state. Energy balance is a potential connection linking FXR and PPARα regulation of autophagy and secretion, 2 seemingly unrelated aspects of hepatocyte function. Conclusions: FXR and PPARα act coordinately to promote energy balance and homeostasis in the liver by regulating autophagy and potentially protein secretion. It is quite likely that their impact extends to additional pathways relevant to hepatic energy balance, and that these pathways will in turn interface with other well-known nutrient-responsive mechanisms of energy control.

scholarly journals Bile Acids Induce the Expression of the Human Peroxisome Proliferator-Activated Receptor α Gene via Activation of the Farnesoid X Receptor

2003 ◽  
Vol 17 (2) ◽  
pp. 259-272 ◽  
Author(s):  
Inés Pineda Torra ◽  
Thierry Claudel ◽  
Caroline Duval ◽  
Vladimir Kosykh ◽  
Jean-Charles Fruchart ◽  
...  
Keyword(s):  
Bile Acids ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

scholarly journals The Human Na+-Taurocholate Cotransporting Polypeptide Gene Is Activated by Glucocorticoid Receptor and Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α, and Suppressed by Bile Acids via a Small Heterodimer Partner-Dependent Mechanism

2006 ◽  
Vol 20 (1) ◽  
pp. 65-79 ◽  
Author(s):  
Jyrki J. Eloranta ◽  
Diana Jung ◽  
Gerd A. Kullak-Ublick
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Human Hepatocytes ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Acid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Small Heterodimer Partner ◽  
Bile Acid Uptake ◽  
Sodium Dependent

Abstract Na+-taurocholate cotransporting polypeptide (NTCP) is the major bile acid uptake system in human hepatocytes. NTCP and the ileal transporter ASBT (apical sodium-dependent bile acid transporter) are two sodium-dependent transporters critical for the enterohepatic circulation of bile acids. The hASBT gene is known to be activated by the glucocorticoid receptor (GR). Here we show that GR also induces the endogenous hNTCP gene and transactivates the reporter-linked hNTCP promoter, in the presence of its ligand dexamethasone. Mutational analysis of the hNTCP promoter identified a functional GR response element, with which GR directly interacts within living cells. The GR/dexamethasone activation of endogenous hNTCP expression was suppressed by bile acids, in a manner dependent on the bile acid receptor farnesoid X receptor. Overexpression of the farnesoid X receptor-inducible transcriptional repressor small heterodimer partner also suppressed the GR/dexamethasone-activation of the hNTCP promoter. The peroxisome proliferator-activated receptor-γ coactivator-1α enhanced the GR/dexamethasone activation of the hNTCP promoter. In conclusion, the hNTCP promoter is activated by GR in a ligand-dependent manner, similarly to the hASBT promoter. Thus, glucocorticoids may coordinately regulate the major bile acid uptake systems in human liver and intestine. The GR/dexamethasone activation of the hNTCP promoter is counteracted by bile acids and small heterodimer partner, providing a negative feedback mechanism for bile acid uptake in human hepatocytes.

scholarly journals Exploration of Hepatoprotective Effect of Gentiopicroside on Alpha-Naphthylisothiocyanate-Induced Cholestatic Liver Injury in Rats by Comprehensive Proteomic and Metabolomic Signatures

2018 ◽  
Vol 49 (4) ◽  
pp. 1304-1319 ◽  
Author(s):  
Han Han ◽  
Lili Xu ◽  
Kai Xiong ◽  
Tong  Zhang ◽  
Zhengtao Wang
Keyword(s):  
Liver Injury ◽  
Bile Acids ◽  
Liver Damage ◽  
Absolute Quantification ◽  
Retinoid X Receptor ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Blood Biochemical ◽  
Isobaric Tags

Background/Aims: Cholestasis is the major cause of the accumulation of bile acids and results in liver damage, fibrosis, and failure. A growing number of studies have shown that gentiopicroside is a promising prospect that may protect the liver. However, its therapeutic mechanism has not yet been clarified. This study aimed to explore the effect and mechanism of gentiopicroside in cholestasis induced by alpha-naphthylisothiocyanate. Methods: We performed isobaric tags for relative and absolute quantification-based quantitative proteomics and metabolomics using liquid chromatography quadruple time-of-fight mass spectrometry and identified the expression of 73 metabolites and 84 proteins associated with cholestasis-related dysfunctions in the metabolism of bile acids, fatty acids, and glycerophospholipids. Results: Integrated analyses of proteomic and metabonomic studies showed altered pathways in cholestasis-induced liver injury involving increased activity of farnesoid X receptor/retinoid X receptor, bile acid biosynthesis, and peroxisome proliferator-activated receptor-α/retinoid X receptor-α. Gentiopicroside could reverse these metabolite, protein, and blood biochemical indices, as well as alleviate liver damage. The progressive changes in the proteins and genes may be correlated with cholestasis and were confirmed by western blot and quantitative realtime polymerase chain reaction. Conclusion: Gentiopicroside could be used to protect the liver in the presence of cholestasis.

The Therapeutic Role of Xenobiotic Nuclear Receptors Against Metabolic Syndrome

2019 ◽  
Vol 20 (1) ◽  
pp. 15-22 ◽  
Author(s):  
Shuqi Pu ◽  
Xiaojie Wu ◽  
Xiaoying Yang ◽  
Yunzhan Zhang ◽  
Yunkai Dai ◽  
...  
Keyword(s):  
Nuclear Receptors ◽  
Metabolic Diseases ◽  
Constitutive Androstane Receptor ◽  
Therapeutic Targets ◽  
Pregnane X Receptor ◽  
Original Data ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose And Lipid Metabolism

Background: Diabetes, with an increased prevalence and various progressive complications, has become a significant global health challenge. The concrete mechanisms responsible for the development of diabetes still remain incompletely unknown, although substantial researches have been conducted to search for the effective therapeutic targets. This review aims to reveal the novel roles of Xenobiotic Nuclear Receptors (XNRs), including the Peroxisome Proliferator-Activated Receptor (PPAR), the Farnesoid X Receptor (FXR), the Liver X Receptor (LXR), the Pregnane X Receptor (PXR) and the Constitutive Androstane Receptor (CAR), in the development of diabetes and provide potential strategies for research and treatment of metabolic diseases. Methods: We retrieved a large number of original data about these five XNRs and organized to focus on their recently discovered functions in diabetes and its complications. Results: Increasing evidences have suggested that PPAR, FXR, LXR ,PXR and CAR are involved in the development of diabetes and its complications through different mechanisms, including the regulation of glucose and lipid metabolism, insulin and inflammation response and related others. Conclusion: PPAR, FXR, LXR, PXR, and CAR, as the receptors for numerous natural or synthetic compounds, may be the most effective therapeutic targets in the treatment of metabolic diseases.

scholarly journals The Management of Cholestatic Liver Diseases: Current Therapies and Emerging New Possibilities

2021 ◽  
Vol 10 (8) ◽  
pp. 1763
Author(s):  
Marta Mazzetti ◽  
Giulia Marconi ◽  
Martina Mancinelli ◽  
Antonio Benedetti ◽  
Marco Marzioni ◽  
...  
Keyword(s):  
Liver Diseases ◽  
Immunosuppressive Drugs ◽  
Farnesoid X Receptor ◽  
New Drugs ◽  
Primary Biliary Cholangitis ◽  
Peroxisome Proliferator ◽  
Biliary Cirrhosis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Multiple Drugs ◽  
New Treatments

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are two chronic cholestatic liver diseases affecting bile ducts that may progress to biliary cirrhosis. In the past few years, the increasing knowledge in the pathogenesis of both diseases led to a growing number of clinical trials and possible new targets for therapy. In this review, we provide an update on the treatments in clinical use and summarize the new drugs in trials for PBC and PSC patients. Farnesoid X Receptor (FXR) agonists and Pan-Peroxisome Proliferator-Activated Receptor (PPAR) agonists are the most promising agents and have shown promising results in both PBC and PSC. Fibroblast Growth Factor 19 (FGF19) analogues also showed good results, especially in PBC, while, although PBC and PSC are autoimmune diseases, immunosuppressive drugs had disappointing effects. Since the gut microbiome could have a potential role in the pathogenesis of PSC, recent research focused on molecules that could change the microbiome, with good results. The near future of the medical management of these diseases may include new treatments or a combination of multiple drugs targeting different signaling pathways at different stages of the diseases.

scholarly journals Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

Molecules ◽  
2019 ◽  
Vol 24 (10) ◽  
pp. 1992 ◽  
Author(s):  
Firas H. Bazzari ◽  
Dalaal M. Abdallah ◽  
Hanan S. El-Abhar
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Chenodeoxycholic Acid ◽  
Insulin Signaling ◽  
Glucose Transporter ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Significant Difference

Insulin resistance is a major risk factor for Alzheimer’s disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aβ42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management.

scholarly journals Post-Translational Modifications of Nuclear Receptors and Human Disease

2012 ◽  
Vol 10 (1) ◽  
pp. nrs.10001 ◽  
Author(s):  
Muralidharan Anbalagan ◽  
Brandy Huderson ◽  
Leigh Murphy ◽  
Brian G. Rowan
Keyword(s):  
Breast Cancer ◽  
Prostate Cancer ◽  
Clinical Outcome ◽  
Nuclear Receptors ◽  
Inflammatory Diseases ◽  
Peroxisome Proliferator ◽  
Additional Measure ◽  
Peroxisome Proliferator Activated Receptor ◽  
Post Translational Modifications ◽  
Pparγ Phosphorylation

Nuclear receptors (NR) impact a myriad of physiological processes including homeostasis, reproduction, development, and metabolism. NRs are regulated by post-translational modifications (PTM) that markedly impact receptor function. Recent studies have identified NR PTMs that are involved in the onset and progression of human diseases, including cancer. The majority of evidence linking NR PTMs with disease has been demonstrated for phosphorylation, acetylation and sumoylation of androgen receptor (AR), estrogen receptor α (ERα), glucocorticoid receptor (GR) and peroxisome proliferator activated receptor γ (PPARΓ). Phosphorylation of AR has been associated with hormone refractory prostate cancer and decreased disease-specific survival. AR acetylation and sumoylation increased growth of prostate cancer tumor models. AR phosphorylation reduced the toxicity of the expanded polyglutamine AR in Kennedy's Disease as a consequence of reduced ligand binding. A comprehensive evaluation of ERα phosphorylation in breast cancer revealed several sites associated with better clinical outcome to tamoxifen therapy, whereas other phosphorylation sites were associated with poorer clinical outcome. ERα acetylation and sumoylation may also have predictive value for breast cancer. GR phosphorylation and acetylation impact GR responsiveness to glucocorticoids that are used as anti-inflammatory drugs. PPARγ phosphorylation can regulate the balance between growth and differentiation in adipose tissue that is linked to obesity and insulin resistance. Sumoylation of PPARγ is linked to repression of inflammatory genes important in patients with inflammatory diseases. NR PTMs provide an additional measure of NR function that can be used as both biomarkers of disease progression, and predictive markers for patient response to NR-directed treatments.

scholarly journals Dietary β-Cryptoxanthin Inhibits High-Refined Carbohydrate Diet–Induced Fatty Liver via Differential Protective Mechanisms Depending on Carotenoid Cleavage Enzymes in Male Mice

2019 ◽  
Vol 149 (9) ◽  
pp. 1553-1564 ◽  
Author(s):  
Ji Ye Lim ◽  
Chun Liu ◽  
Kang-Quan Hu ◽  
Donald E Smith ◽  
Dayong Wu ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Farnesoid X Receptor ◽  
Receptor Protein ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Double Knockout ◽  
Carbohydrate Diet ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver ◽  
Β Carotene

ABSTRACT Background β-Cryptoxanthin (BCX), a provitamin A carotenoid shown to protect against nonalcoholic fatty liver disease (NAFLD), can be cleaved by β-carotene-15,15′-oxygenase (BCO1) to generate vitamin A, and by β-carotene-9′,10′-oxygenase (BCO2) to produce bioactive apo-carotenoids. BCO1/BCO2 polymorphisms have been associated with variations in plasma carotenoid amounts in both humans and animals. Objectives We investigated whether BCX feeding inhibits high refined-carbohydrate diet (HRCD)-induced NAFLD, dependent or independent of BCO1/BCO2. Methods Six-week-old male wild-type (WT) and BCO1−/−/BCO2−/− double knockout (DKO) mice were randomly fed HRCD (66.5% of energy from carbohydrate) with or without BCX (10 mg/kg diet) for 24 wk. Pathological and biochemical variables were analyzed in the liver and mesenteric adipose tissues (MATs). Data were analyzed by 2-factor ANOVA. Results Compared to their respective HRCD controls, BCX reduced hepatic steatosis severity by 33‒43% and hepatic total cholesterol by 43‒70% in both WT and DKO mice (P < 0.01). Hepatic concentrations of BCX, but not retinol and retinyl palmitate, were 33-fold higher in DKO mice than in WT mice (P < 0.001). BCX feeding increased the hepatic fatty acid oxidation protein peroxisome proliferator-activated receptor-α, and the cholesterol efflux gene ATP-binding cassette transporter5, and suppressed the lipogenesis gene acetyl-CoA carboxylase 1 (Acc1) in the MAT of WT mice but not DKO mice (P < 0.05). BCX feeding decreased the hepatic lipogenesis proteins ACC and stearoyl-CoA desaturase-1 (3-fold and 5-fold) and the cholesterol synthesis genes 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and HMG-CoA synthase 1 (2.7-fold and 1.8-fold) and increased the cholesterol catabolism gene cholesterol 7α-hydroxylase (1.9-fold) in the DKO but not WT mice (P < 0.05). BCX feeding increased hepatic protein sirtuin1 (2.5-fold) and AMP-activated protein kinase (9-fold) and decreased hepatic farnesoid X receptor protein (80%) and the inflammatory cytokine gene Il6 (6-fold) in the MAT of DKO mice but not WT mice (P < 0.05). Conclusion BCX feeding mitigates HRCD-induced NAFLD in both WT and DKO mice through different mechanisms in the liver-MAT axis, depending on the presence or absence of BCO1/BCO2.

scholarly journals A triple farnesoid X receptor and peroxisome proliferator-activated receptor α/δ activator reverses hepatic fibrosis in diet-induced NASH in mice

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Pascal Heitel ◽  
Giuseppe Faudone ◽  
Moritz Helmstädter ◽  
Jurema Schmidt ◽  
Astrid Kaiser ◽  
...  
Keyword(s):  
Hepatic Fibrosis ◽  
Single Molecule ◽  
Farnesoid X Receptor ◽  
Peroxisome Proliferator ◽  
Target Engagement ◽  
Hepatic Inflammation ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Metabolic Syndrome ◽  
Nash Strategies

AbstractNon-alcoholic steatohepatitis (NASH) - a hepatic manifestation of the metabolic syndrome - is a multifactorial disease with alarming global prevalence. It involves steatosis, inflammation and fibrosis in the liver, thus demanding multiple modes of action for robust therapeutic efficacy. Aiming to fuse complementary validated anti-NASH strategies in a single molecule, we have designed and systematically optimized a scaffold for triple activation of farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR) α and PPARδ. Pilot profiling of the resulting triple modulator demonstrated target engagement in native cellular settings and in mice, rendering it a suitable tool to probe the triple modulator concept in vivo. In DIO NASH in mice, the triple agonist counteracted hepatic inflammation and reversed hepatic fibrosis highlighting the potential of designed polypharmacology in NASH.

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