Bile Acids Acutely Stimulate Insulin Secretion of Mouse  -Cells via Farnesoid X Receptor Activation and KATP Channel Inhibition

Cholestasis is a kind of stressful syndrome along with liver toxicity, which has been demonstrated to be related to fibrosis, cirrhosis, even cholangiocellular or hepatocellular carcinomas. Cholestasis usually caused by the dysregulated metabolism of bile acids that possess high cellular toxicity and synthesized by cholesterol in the liver to undergo enterohepatic circulation. In cholestasis, the accumulation of bile acids in the liver causes biliary and hepatocyte injury, oxidative stress, and inflammation. The farnesoid X receptor (FXR) is regarded as a bile acid–activated receptor that regulates a network of genes involved in bile acid metabolism, providing a new therapeutic target to treat cholestatic diseases. Arbutin is a glycosylated hydroquinone isolated from medicinal plants in the genus Arctostaphylos, which has a variety of potentially pharmacological properties, such as anti-inflammatory, antihyperlipidemic, antiviral, antihyperglycemic, and antioxidant activity. However, the mechanistic contributions of arbutin to alleviate liver injury of cholestasis, especially its role on bile acid homeostasis via nuclear receptors, have not been fully elucidated. In this study, we demonstrate that arbutin has a protective effect on α-naphthylisothiocyanate–induced cholestasis via upregulation of the levels of FXR and downstream enzymes associated with bile acid homeostasis such as Bsep, Ntcp, and Sult2a1, as well as Ugt1a1. Furthermore, the regulation of these functional proteins related to bile acid homeostasis by arbutin could be alleviated by FXR silencing in L-02 cells. In conclusion, a protective effect could be supported by arbutin to alleviate ANIT-induced cholestatic liver toxicity, which was partly through the FXR pathway, suggesting arbutin may be a potential chemical molecule for the cholestatic disease.

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Regulation of taurine conjugation and biosynthesis by bile acids through farnesoid X receptor activation

Hepatology Research ◽

10.1111/hepr.12290 ◽

2014 ◽

Vol 44 (10) ◽

pp. E1-E2 ◽

Cited By ~ 3

Author(s):

Teruo Miyazaki ◽

Akira Honda ◽

Yasushi Matsuzaki

Keyword(s):

Bile Acids ◽

Receptor Activation ◽

Farnesoid X Receptor

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Vertical Sleeve Gastrectomy Induces Enteroendocrine Cell Differentiation of Intestinal Stem Cells Through Farnesoid X Receptor Activation

10.1101/2021.04.22.440705 ◽

2021 ◽

Author(s):

Ki-Suk Kim ◽

Bailey C. E. Peck ◽

Yu-Han Hung ◽

Kieran Koch-Laskowski ◽

Landon Wood ◽

...

Keyword(s):

Sleeve Gastrectomy ◽

Bile Acid ◽

Bile Acids ◽

Energy Homeostasis ◽

Receptor Activation ◽

Farnesoid X Receptor ◽

Vertical Sleeve Gastrectomy ◽

Gut Peptides ◽

Intestinal Differentiation ◽

Intestinal Organoids

AbstractVertical sleeve gastrectomy (VSG) is one of several bariatric procedures that substantially improves glycemia and energy homeostasis. Increased secretion of multiple gut peptides has been hypothesized to be a critical contributor to VSG’s potent effects to reduce body weight and improve glucose regulation. VSG results in an increase in the number of hormone-secreting enteroendocrine cells (EECs) in the intestinal epithelium, but whether this increase is via proliferation or differentiation of EECs and their subtypes remains unclear. Notably, the beneficial effects of VSG are lost in a mouse model lacking the bile acid nuclear receptor, farnesoid X receptor (FXR). FXR is a nuclear transcription factor that has been shown to regulate intestinal stem cell (ISC) function in cancer models, but whether it plays a role specifically in normal intestinal differentiation remains unknown. Therefore, we hypothesized that the VSG-induced increase in EECs is due to changes in intestinal differentiation driven by an increase in bile acid signaling through FXR. To test this, we performed VSG in mice that express eGFP in ISC/progenitor cells and performed RNAseq on GFP-positive cells sorted from the intestinal epithelia. We also assessed changes in EEC number (marked by GLP-1) in mouse intestinal organoids following treatment with bile acids and/or an FXR antagonist. RNA-seq revealed that FXR is expressed in ISCs and that VSG explicitly alters ISC expression of several genes that regulate intestinal secretory cell development, including EEC differentiation. Mouse intestinal organoids treated with bile acids increased GLP-1-positive cell numbers, whereas a potent FXR antagonist blocked this effect. Taken together, these data indicate that VSG drives ISC fate towards EEC differentiation through FXR signaling.

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Quercetin Stimulates Insulin Secretion and Reduces the Viability of Rat INS-1 Beta-Cells

Cellular Physiology and Biochemistry ◽

10.1159/000445623 ◽

2016 ◽

Vol 39 (1) ◽

pp. 278-293 ◽

Cited By ~ 26

Author(s):

Michael Kittl ◽

Marlena Beyreis ◽

Munkhtuya Tumurkhuu ◽

Johannes Fürst ◽

Katharina Helm ◽

...

Keyword(s):

Insulin Secretion ◽

Cell Viability ◽

Beta Cells ◽

Insulin Release ◽

Katp Channel ◽

Annexin V ◽

Long Term Effects ◽

Mean Cell Volume ◽

Channel Inhibition

Background/Aims: Previously we described insulinotropic effects of Leonurus sibiricus L. plant extracts used for diabetes mellitus treatment in Traditional Mongolian Medicine. The flavonoid quercetin and its glycoside rutin, which exert anti-diabetic properties in vivo by interfering with insulin signaling in peripheral target tissues, are constituents of these extracts. This study was performed to better understand short- and long-term effects of quercetin and rutin on beta-cells. Methods: Cell viability, apoptosis, phospho-protein abundance and insulin release were determined using resazurin, annexin-V binding assays, Western blot and ELISA, respectively. Membrane potentials (Vmem), whole-cell Ca2+ (ICa)- and ATP-sensitive K+ (IKATP) currents were measured by patch clamp. Intracellular Ca2+ (Cai) levels were measured by time-lapse imaging using the ratiometric Ca2+ indicator Fura-2. Results: Rutin, quercetin and the phosphoinositide-3-kinase (PI3K) inhibitor LY294002 caused a dose-dependent reduction in cell viability with IC50 values of ∼75 µM, ∼25 µM and ∼3.5 µM, respectively. Quercetin (50 µM) significantly increased the percentage of Annexin-V+ cells within 48 hrs. The mean cell volume (MCV) of quercetin-treated cells was significantly lower. Within 2 hrs, quercetin significantly decreased basal- and insulin-stimulated Akt(T308) phosphorylation and increased Erk1/2 phosphorylation, without affecting P-Akt(S473) abundance. Basal- and glucose-stimulated insulin release were significantly stimulated by quercetin. Quercetin significantly depolarized Vmem by ∼25 mV which was prevented by the KATP-channel opener diazoxide, but not by the L-type ICa inhibitor nifedipine. Quercetin significantly stimulated ICa and caused a 50% inhibition of IKATP. The effects on Vmem, ICa and IKATP rapidly reached peak values and then gradually diminished to control values within ∼1 minute. With a similar time-response quercetin induced an elevation in Cai which was completely abolished in the absence of Ca2+ in the bath solution. Rutin (50 µM) did not significantly alter the percentage of Annexin-V+ cells, MCV, Akt or Erk1/2 phosphorylation, insulin secretion, or the electrophysiological behavior of INS-1 cells. Conclusion: We conclude that quercetin acutely stimulates insulin release, presumably by transient KATP channel inhibition and ICa stimulation. Long term application of quercetin inhibits cell proliferation and induces apoptosis, most likely by inhibition of PI3K/Akt signaling.

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Faculty Opinions recommendation of Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726472318.793524662 ◽

2016 ◽

Author(s):

Grace Guo

Keyword(s):

Bile Acid ◽

Acid Composition ◽

Reverse Cholesterol Transport ◽

Cholesterol Absorption ◽

Receptor Activation ◽

Farnesoid X Receptor ◽

Cholesterol Transport

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Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

Scientific Reports ◽

10.1038/s41598-021-90687-5 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lori W. E. van der Schoor ◽

Henkjan J. Verkade ◽

Anna Bertolini ◽

Sanne de Wit ◽

Elvira Mennillo ◽

...

Keyword(s):

Bile Acids ◽

Treatment Options ◽

Preventive Treatment ◽

Neonatal Hyperbilirubinemia ◽

Farnesoid X Receptor ◽

Neurological Damage ◽

Obeticholic Acid ◽

Protein Levels ◽

Gunn Rats ◽

Plasma Bilirubin

AbstractNeonatal hyperbilirubinemia or jaundice is associated with kernicterus, resulting in permanent neurological damage or even death. Conventional phototherapy does not prevent hyperbilirubinemia or eliminate the need for exchange transfusion. Here we investigated the potential of therapeutic bile acids ursodeoxycholic acid (UDCA) and obeticholic acid (OCA, 6-α-ethyl-CDCA), a farnesoid-X-receptor (FXR) agonist, as preventive treatment options for neonatal hyperbilirubinemia using the hUGT1*1 humanized mice and Ugt1a-deficient Gunn rats. Treatment of hUGT1*1 mice with UDCA or OCA at postnatal days 10–14 effectively decreased bilirubin in plasma (by 82% and 62%) and brain (by 72% and 69%), respectively. Mechanistically, our findings indicate that these effects are mediated through induction of protein levels of hUGT1A1 in the intestine, but not in liver. We further demonstrate that in Ugt1a-deficient Gunn rats, UDCA but not OCA significantly decreases plasma bilirubin, indicating that at least some of the hypobilirubinemic effects of UDCA are independent of UGT1A1. Finally, using the synthetic, non-bile acid, FXR-agonist GW4064, we show that some of these effects are mediated through direct or indirect activation of FXR. Together, our study shows that therapeutic bile acids UDCA and OCA effectively reduce both plasma and brain bilirubin, highlighting their potential in the treatment of neonatal hyperbilirubinemia.

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Role of Bile Acids in the Regulation of Food Intake, and Their Dysregulation in Metabolic Disease

Nutrients ◽

10.3390/nu13041104 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1104

Author(s):

Cong Xie ◽

Weikun Huang ◽

Richard L. Young ◽

Karen L. Jones ◽

Michael Horowitz ◽

...

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Peptide Yy ◽

Glycogen Synthesis ◽

Hormone Secretion ◽

Gastrointestinal Hormones ◽

Farnesoid X Receptor ◽

Gastrointestinal Hormone ◽

Bile Acid Sequestrants

Bile acids are cholesterol-derived metabolites with a well-established role in the digestion and absorption of dietary fat. More recently, the discovery of bile acids as natural ligands for the nuclear farnesoid X receptor (FXR) and membrane Takeda G-protein-coupled receptor 5 (TGR5), and the recognition of the effects of FXR and TGR5 signaling have led to a paradigm shift in knowledge regarding bile acid physiology and metabolic health. Bile acids are now recognized as signaling molecules that orchestrate blood glucose, lipid and energy metabolism. Changes in FXR and/or TGR5 signaling modulates the secretion of gastrointestinal hormones including glucagon-like peptide-1 (GLP-1) and peptide YY (PYY), hepatic gluconeogenesis, glycogen synthesis, energy expenditure, and the composition of the gut microbiome. These effects may contribute to the metabolic benefits of bile acid sequestrants, metformin, and bariatric surgery. This review focuses on the role of bile acids in energy intake and body weight, particularly their effects on gastrointestinal hormone secretion, the changes in obesity and T2D, and their potential relevance to the management of metabolic disorders.

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Recent advances in understanding bile acid homeostasis

F1000Research ◽

10.12688/f1000research.12449.1 ◽

2017 ◽

Vol 6 ◽

pp. 2029 ◽

Cited By ~ 52

Author(s):

John YL Chiang

Keyword(s):

Bile Acid ◽

Bile Acids ◽

Acid Synthesis ◽

Bile Acid Synthesis ◽

Farnesoid X Receptor ◽

Recent Advances ◽

Bile Acid Pool Size ◽

Bile Acid Receptor ◽

Acid Toxicity ◽

G Protein Coupled

Bile acids are derived from cholesterol to facilitate intestinal nutrient absorption and biliary secretion of cholesterol. Recent studies have identified bile acids as signaling molecules that activate nuclear farnesoid X receptor (FXR) and membrane G protein-coupled bile acid receptor-1 (Gpbar-1, also known as TGR5) to maintain metabolic homeostasis and protect liver and other tissues and cells from bile acid toxicity. Bile acid homeostasis is regulated by a complex mechanism of feedback and feedforward regulation that is not completely understood. This review will cover recent advances in bile acid signaling and emerging concepts about the classic and alternative bile acid synthesis pathway, bile acid composition and bile acid pool size, and intestinal bile acid signaling and gut microbiome in regulation of bile acid homeostasis.

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Bile Acids Induce Platelet Activation Leading to Degranulation and a Prothrombotic Phenotype

Blood ◽

10.1182/blood-2019-126095 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4887-4887

Author(s):

Joachim Zobel ◽

Tanja Strini ◽

Martin Tischitz ◽

Sina Pohl ◽

Theresa Greimel ◽

...

Keyword(s):

Liver Fibrosis ◽

Bile Acids ◽

Conflicts Of Interest ◽

Annexin V ◽

Farnesoid X Receptor ◽

Fibrinogen Binding ◽

Model Study ◽

Serine Protease Activity ◽

Adult Volunteers ◽

Dose Dependent

Background: Previous articles have identified the farnesoid X receptor (FXR) as an integral part in the formation of coated platelets. Coated platelets are preactivated platelets featuring degranulation, increased fibrinogen binding, and increased serine protease activity leading to fibrin generation. Furthermore, phosphatidylserine exposure is increased and integrin α2bβIII is inhibited - leading to a prothrombotic phenotype despite decreased platelet aggregation. We hypothesize that bile acids, as natural ligands of FXR, lead to a change of platelet phenotype and therefore play a pivotal role in the formation of coated platelets, especially in presence of cholestasis. Methods: Based on previous findings, we incubated human washed platelets of healthy adult volunteers with the synthetic FXR ligand GW4064 in various concentrations (0, 10, 20, 50, 100µM) and used flow cytometry to detect a shift in p-selectin expression, PAC-1 binding and annexin-V-binding. Moreover, we used different concentrations (0, 100, 200, 400, 600µM) of three bile acids (ursodeoxycholic acid, UDCA; chenodeoxycholic acid, CDCA; glycochenodeoxycholic acid, GCDCA) to see if natural FXR ligands induce an effect on the platelet phenotype. Results: We observed a dose dependent shift in annexin-V-binding when treating washed platelets with GW4064 as well as CDCA and GCDCA. Similarly, GW4064 led to increased p-selectin expression while increased PAC-1-binding was only detected at the highest concentration. In contrast, CDCA and GCDCA showed merely slight changes in p-selectin expression whereas PAC-1-binding seemed to be unaffected. However, none of these effects were seen when using UDCA. Conclusion: We conclude that pretreatment of washed platelets with CDCA and GCDCA initiate a dose-dependent shift towards a prothrombotic platelet phenotype. Therefore, we assume that increased levels of certain bile acids drive thrombosis in patients with cholestatic liver injury. Furthermore, a recent mouse model study suggested that platelet derived growth factor β (PDGFβ), a component of α-granula, drives liver fibrosis. Hence, in addition to their prothrombotic effects, coated platelets might exacerbate liver fibrosis. Disclosures No relevant conflicts of interest to declare.

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