Potential of therapeutic bile acids in the treatment of neonatal Hyperbilirubinemia

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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Farnesoid X receptor and bile acids regulate vitamin A storage

Scientific Reports ◽

10.1038/s41598-019-55988-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Ali Saeed ◽

Jing Yang ◽

Janette Heegsma ◽

Albert K. Groen ◽

Saskia W. C. van Mil ◽

...

Keyword(s):

Vitamin A ◽

Bile Acids ◽

Mouse Liver ◽

Retinyl Palmitate ◽

Farnesoid X Receptor ◽

Immune Control ◽

Obeticholic Acid ◽

Vitamin A Metabolism ◽

Protein Levels ◽

And Storage

AbstractThe nuclear receptor Farnesoid X Receptor (FXR) is activated by bile acids and controls multiple metabolic processes, including bile acid, lipid, carbohydrate, amino acid and energy metabolism. Vitamin A is needed for proper metabolic and immune control and requires bile acids for efficient intestinal absorption and storage in the liver. Here, we analyzed whether FXR regulates vitamin A metabolism. Compared to control animals, FXR-null mice showed strongly reduced (>90%) hepatic levels of retinol and retinyl palmitate and a significant reduction in lecithin retinol acyltransferase (LRAT), the enzyme responsible for hepatic vitamin A storage. Hepatic reintroduction of FXR in FXR-null mice induced vitamin A storage in the liver. Hepatic vitamin A levels were normal in intestine-specific FXR-null mice. Obeticholic acid (OCA, 3 weeks) treatment rapidly reduced (>60%) hepatic retinyl palmitate levels in mice, concurrent with strongly increased retinol levels (>5-fold). Similar, but milder effects were observed in cholic acid (12 weeks)-treated mice. OCA did not change hepatic LRAT protein levels, but strongly reduced all enzymes involved in hepatic retinyl ester hydrolysis, involving mostly post-transcriptional mechanisms. In conclusion, vitamin A metabolism in the mouse liver heavily depends on the FXR and FXR-targeted therapies may be prone to cause vitamin A-related pathologies.

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FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver

The Journal of Lipid Research ◽

10.1194/jlr.m081935 ◽

2018 ◽

Vol 59 (6) ◽

pp. 982-993 ◽

Cited By ~ 22

Author(s):

Romeo Papazyan ◽

Xueqing Liu ◽

Jingwen Liu ◽

Bin Dong ◽

Emily M. Plummer ◽

...

Keyword(s):

Target Gene ◽

Ldl Cholesterol ◽

Ldl Receptor ◽

Hdl Cholesterol ◽

Farnesoid X Receptor ◽

Receptor Protein ◽

Chimeric Mice ◽

Obeticholic Acid ◽

Protein Levels ◽

Mechanistic Basis

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

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A 10-gene prognostic signature points to LIMCH1 and HLA-DQB1 as important players in aggressive cervical cancer disease

British Journal of Cancer ◽

10.1038/s41416-021-01305-0 ◽

2021 ◽

Author(s):

Mari K. Halle ◽

Marte Sødal ◽

David Forsse ◽

Hilde Engerud ◽

Kathrine Woie ◽

...

Keyword(s):

Cervical Cancer ◽

Primary Tumour ◽

Treatment Options ◽

Prognostic Significance ◽

Gene Signature ◽

Prognostic Impact ◽

Cancer Disease ◽

Gene Set ◽

Patient Cohort ◽

Protein Levels

Abstract Background Advanced cervical cancer carries a particularly poor prognosis, and few treatment options exist. Identification of effective molecular markers is vital to improve the individualisation of treatment. We investigated transcriptional data from cervical carcinomas related to patient survival and recurrence to identify potential molecular drivers for aggressive disease. Methods Primary tumour RNA-sequencing profiles from 20 patients with recurrence and 53 patients with cured disease were compared. Protein levels and prognostic impact for selected markers were identified by immunohistochemistry in a population-based patient cohort. Results Comparison of tumours relative to recurrence status revealed 121 differentially expressed genes. From this gene set, a 10-gene signature with high prognostic significance (p = 0.001) was identified and validated in an independent patient cohort (p = 0.004). Protein levels of two signature genes, HLA-DQB1 (n = 389) and LIMCH1 (LIM and calponin homology domain 1) (n = 410), were independent predictors of survival (hazard ratio 2.50, p = 0.007 for HLA-DQB1 and 3.19, p = 0.007 for LIMCH1) when adjusting for established prognostic markers. HLA-DQB1 protein expression associated with programmed death ligand 1 positivity (p < 0.001). In gene set enrichment analyses, HLA-DQB1high tumours associated with immune activation and response to interferon-γ (IFN-γ). Conclusions This study revealed a 10-gene signature with high prognostic power in cervical cancer. HLA-DQB1 and LIMCH1 are potential biomarkers guiding cervical cancer treatment.

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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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Farnesoid X Receptor an Emerging Target to Combat Obesity

Digestive Diseases ◽

10.1159/000450909 ◽

2017 ◽

Vol 35 (3) ◽

pp. 185-190 ◽

Cited By ~ 18

Author(s):

C. Daniel De Magalhaes Filho ◽

Michael Downes ◽

Ronald M. Evans

Keyword(s):

Type 2 Diabetes ◽

Bile Acid ◽

Treatment Options ◽

Farnesoid X Receptor ◽

Whole Body ◽

Body Lipid ◽

Associated Diseases ◽

Attractive Candidate ◽

Potential Use

Obesity and its associated diseases, including type 2 diabetes, have reached epidemic levels worldwide. However, available treatment options are limited and ineffective in managing the disease. There is therefore an urgent need for the development of new pharmacological solutions. The bile acid (BA) Farnesoid X receptor (FXR) has recently emerged as an attractive candidate. Initially described for their role in lipid and vitamin absorption from diet, BAs are hormones with powerful effects on whole body lipid and glucose metabolism. In this review, we focus on FXR and how 2 decades of work on this receptor, both in rodents and humans, have led to the development of drug agonists with potential use in humans for treatment of conditions ranging from obesity-associated diseases to BA dysregulation.

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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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Effect of ursodeoxycholic acid on lipid metabolism: through the prism of evidence from 2019.

Herald of Pancreatic Club ◽

10.33149/vkp.2020.01.11 ◽

2020 ◽

Vol 46 (1) ◽

pp. 83-88

Author(s):

N. B. Gubergrits ◽

N.V. Byelyayeva ◽

T. L. Mozhyna ◽

G. M. Lukashevich ◽

P. G. Fomenko

Keyword(s):

Lipid Metabolism ◽

Bile Acid ◽

Bile Acids ◽

De Novo ◽

Gallstone Disease ◽

Farnesoid X Receptor ◽

Synthesis Rate ◽

Primary Biliary Cholangitis ◽

Fractional Synthesis Rate ◽

Fractional Synthesis

After the discovery of the method of ursodeoxycholic acid’s (UDCA) synthesis and the publication of evidence confirming its ability to reduce the lithogenic properties of bile, active clinical use of UDCA began in the world. This drug, which has pleiotropic effect (choleretic, cytoprotective, immunomodulatory, antiapoptic, litholytic, hypocholesterolemic), has proven its effectiveness in the treatment various diseases: primary biliary cholangitis, intrahepatic cholestasis of pregnancy, gallstone disease. Being a tertiary bile acid, UDCA stimulates bile acid synthesis by reducing the circulating fibroblast growth factor 19 and inhibiting the activation of the farnesoid X-receptor (FXR), which leads to the induction of cholesterol-7α-hydroxylase, a key enzyme in the synthesis of bile acid de novo, mediating the conversion of cholesterol into bile acids. Changes in the formation of bile acids and cholesterol while taking UDCA intake is accompanied by activation of the main enzyme of cholesterol synthesis - 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Under the influence of UDCA the activity of stearoyl-Coa desaturase (SCD) in visceral white adipose tissue increases. According to studies conducted in 2019, UDCA improves lipid metabolism by regulating the activity of the ACT/mTOR signaling pathway, reduces the synthesis of cholesterol, decreases the fractional synthesis rate of cholesterol and the fractional synthesis rate of triglycerides. It has been proved that UDCA is accompanied by a decrease in the level of total cholesterol and low density lipoprotein cholesterol.

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Migraine

International Journal for Research in Applied Science and Engineering Technology ◽

10.22214/ijraset.2021.39486 ◽

2021 ◽

Vol 9 (12) ◽

pp. 1407-1427

Author(s):

Mr. Ghene Mauli Ganesh

Keyword(s):

Chronic Migraine ◽

Medication Overuse ◽

Treatment Options ◽

Preventive Treatment ◽

Primary Headaches ◽

Brain Disorder ◽

Current State ◽

The Common ◽

Chronic Headaches ◽

Migrainous Headache

Abstract: Migraine is the most common disabling brain disorder. Chronic migraine, a condition characterized by the experience of migrainous headache on at least 15 days per month, is highly disabling. Patients with chronic migraine present to primary care, are often referred for management to secondary care, and make up a large proportion of patients in specialist headache clinics. Many patients with chronic migraine also have medication overuse, defined as using a compound analgesic, opioid, triptan or ergot derivative on at least 10 days per month. All doctors will encounter patients with chronic headaches. A basic working knowledge of the common primary headaches, and a rational manner of approaching the patient with these conditions, allows a specific diagnosis of chronic migraine to be made quickly and safely, and by making this diagnosis one opens up a substantial number of acute and preventive treatment options. This article discusses the current state of management of chronic migraine.

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Bile Acids and Nonalcoholic Fatty Liver and Pancreas Disease: Going Together?

Doctor Ru ◽

10.31550/1727-2378-2020-19-7-21-30 ◽

2020 ◽

Vol 19 (7) ◽

pp. 21-30

Author(s):

N.B. Gubergritz ◽

◽

N.V. Belyaeva ◽

T.L. Mozhina ◽

N.E. Monogarova ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Ursodeoxycholic Acid ◽

Nonalcoholic Fatty Liver Disease ◽

Bile Acids ◽

Fatty Liver Disease ◽

Farnesoid X Receptor ◽

Pancreas Disease ◽

Nonalcoholic Fatty Liver ◽

Fatty Pancreas

Objective of the Review: to analyse changes in bile acids (BA) metabolism due to nonalcoholic fatty liver disease (NAFL), nonalcoholic fatty pancreas disease (NAFP); to assess the efficiency of ursodeoxycholic acid (UDCA) for their correction. Key Points. NAFL and NAFP have much in common, including BA synthesis imbalance and reduced farnesoid X receptor (FXR) expression. One possible therapy of NAFL and NAFP is BA synthesis correction and increase in FXR expression using FXR agonists. The article discusses clinical and experimental trials of the efficiency of selective FXR agonist — UDCA — in NAFL and NAFP. Conclusion. The multifactorial UDCA mechanism of action including anti-inflammatory, antioxidant, cytoprotective and antiapoptotic actions, can normalise carbohydrate, lipid metabolism and activate FXR; it can justify medicine inclusion into NAFL and NAFP therapeutic regimens. Keywords: nonalcoholic fatty liver disease, nonalcoholic fatty pancreas disease, ursodeoxycholic acid.

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