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John Y. L. Chiang - One of the best experts on this subject based on the ideXlab platform.

  • farnesoid x receptor induces takeda g protein receptor 5 cross talk to regulate Bile Acid Synthesis and hepatic metabolism
    Journal of Biological Chemistry, 2017
    Co-Authors: Preeti Pathak, Shannon Boehme, Frank J Gonzalez, Kristopher W Krausz, John Y. L. Chiang
    Abstract:

    Abstract The Bile Acid-activated receptors, nuclear farnesoid X receptor (FXR) and the membrane Takeda G-protein receptor 5 (TGR5), are known to improve glucose and insulin sensitivity in obese and diabetic mice. However, the metabolic roles of these two receptors and the underlying mechanisms are incompletely understood. Here we studied the effects of the dual FXR and TGR5 agonist INT-767 on hepatic Bile Acid Synthesis and intestinal secretion of glucagon-like peptide-1 (GLP-1) in wild type, Fxr-/-, and Tgr5-/- mice. INT-767 efficaciously stimulated intracellular Ca2+ levels, cAMP activity, and GLP-1 secretion and improved glucose and lipid metabolism more than did the FXR-selective obeticholic Acid and TGR5-selective INT-777 agonists. Interestingly, INT-767 reduced expression of the genes in the classic Bile Acid Synthesis pathway but induced those in the alternative pathway, which is consistent with decreased tauro-cholic Acid and increased tauro-muricholic Acids in Bile. Furthermore, FXR activation induced expression of FXR target genes including fibroblast growth factor 15, and unexpectedly Tgr5 and prohormone convertase 1/3 gene expression in the ileum. We identified an FXR responsive element on the Tgr5 gene promoter. Fxr-/- and Tgr5-/- mice exhibited reduced GLP-1 secretion, which was stimulated by INT-767 in the Tgr5-/- mice but not in the Fxr-/- mice. Our findings uncovered a novel mechanism in which INT-767 activation of FXR induces Tgr5 gene expression and increases Ca2+ levels and cAMP activity to stimulate GLP-1 secretion and improve hepatic glucose and lipid metabolism in high fat diet-induced obese mice. Activation of both FXR and TGR5 therefore, may represent an effective therapy for managing hepatic steatosis, obesity and diabetes.

  • mechanism of tissue specific farnesoid x receptor in suppressing the expression of genes in Bile Acid Synthesis in mice
    Hepatology, 2012
    Co-Authors: Bo Kong, John Y. L. Chiang, Li Wang, Youcai Zhang, Curtis D Klaassen
    Abstract:

    Activation of farnesoid X receptor (Fxr, Nr1h4) is a major mechanism in suppressing Bile-Acid Synthesis by reducing the expression levels of genes encoding key Bile-Acid synthetic enzymes (e.g., cytochrome P450 [CYP]7A1/Cyp7a1 and CYP8B1/Cyp8b1). FXR-mediated induction of hepatic small heterodimer partner (SHP/Shp, Nr0b2) and intestinal fibroblast growth factor 15 (Fgf15; FGF19 in humans) has been shown to be responsible for this suppression. However, the exact contribution of Shp/Fgf15 to this suppression, and the associated cell-signaling pathway, is unclear. By using novel genetically modified mice, the current study showed that the intestinal Fxr/Fgf15 pathway was critical for suppressing both Cyp7a1 and Cyp8b1 gene expression, but the liver Fxr/Shp pathway was important for suppressing Cyp8b1 gene expression and had a minor role in suppressing Cyp7a1 gene expression. Furthermore, in vivo administration of Fgf15 protein to mice led to a strong activation of extracellular signal-related kinase (ERK) and, to a smaller degree, Jun N-terminal kinase (JNK) in the liver. In addition, deficiency of either the ERK or JNK pathway in mouse livers reduced the basal, but not the Fgf15-mediated, suppression of Cyp7a1 and Cyp8b1 gene expression. However, deficiency of both ERK and JNK pathways prevented Fgf15-mediated suppression of Cyp7a1 and Cyp8b1 gene expression. Conclusion: The current study clearly elucidates the underlying molecular mechanism of hepatic versus intestinal Fxr in regulating the expression of genes critical for Bile-Acid Synthesis and hydrophobicity in the liver. (HEPATOLOGY 2012;56:1034–1043)

  • glucose and insulin induction of Bile Acid Synthesis mechanisms and implication in diabetes and obesity
    Journal of Biological Chemistry, 2012
    Co-Authors: Jessica M Francl, Youcai Zhang, Curtis D Klaassen, Shannon Boehme, Adrian Ochoa, Sandra K Erickson, John Y. L. Chiang
    Abstract:

    Bile Acids facilitate postprandial absorption of nutrients. Bile Acids also activate the farnesoid X receptor (FXR) and the G protein-coupled receptor TGR5 and play a major role in regulating lipid, glucose, and energy metabolism. Transgenic expression of cholesterol 7α-hydroxylase (CYP7A1) prevented high fat diet-induced diabetes and obesity in mice. In this study, we investigated the nutrient effects on Bile Acid Synthesis. Refeeding of a chow diet to fasted mice increased CYP7A1 expression, Bile Acid pool size, and serum Bile Acids in wild type and humanized CYP7A1-transgenic mice. Chromatin immunoprecipitation assays showed that glucose increased histone acetylation and decreased histone methylation on the CYP7A1 gene promoter. Refeeding also induced CYP7A1 in fxr-deficient mice, indicating that FXR signaling did not play a role in postprandial regulation of Bile Acid Synthesis. In streptozocin-induced type I diabetic mice and genetically obese type II diabetic ob/ob mice, hyperglycemia increased histone acetylation status on the CYP7A1 gene promoter, leading to elevated basal Cyp7a1 expression and an enlarged Bile Acid pool with altered Bile Acid composition. However, refeeding did not further increase CYP7A1 expression in diabetic mice. In summary, this study demonstrates that glucose and insulin are major postprandial factors that induce CYP7A1 gene expression and Bile Acid Synthesis. Glucose induces CYP7A1 gene expression mainly by epigenetic mechanisms. In diabetic mice, CYP7A1 chromatin is hyperacetylated, and fasting to refeeding response is impaired and may exacerbate metabolic disorders in diabetes.

  • regulation of Bile Acid and cholesterol metabolism by ppars
    Ppar Research, 2009
    Co-Authors: Tiangang Li, John Y. L. Chiang
    Abstract:

    Bile Acids are amphipathic molecules synthesized from cholesterol in the liver. Bile Acid Synthesis is a major pathway for hepatic cholesterol catabolism. Bile Acid Synthesis generates Bile flow which is important for biliary secretion of free cholesterol, endogenous metabolites, and xenobiotics. Bile Acids are biological detergents that facilitate intestinal absorption of lipids and fat-soluble vitamins. Recent studies suggest that Bile Acids are important metabolic regulators of lipid, glucose, and energy homeostasis. Agonists of peroxisome proliferator-activated receptors (PPARα, PPARγ, PPARδ) regulate lipoprotein metabolism, fatty Acid oxidation, glucose homeostasis and inflammation, and therefore are used as anti-diabetic drugs for treatment of dyslipidemia and insulin insistence. Recent studies have shown that activation of PPARα alters Bile Acid Synthesis, conjugation, and transport, and also cholesterol Synthesis, absorption and reverse cholesterol transport. This review will focus on the roles of PPARs in the regulation of pathways in Bile Acid and cholesterol homeostasis, and the therapeutic implications of using PPAR agonists for the treatment of metabolic syndrome.

  • Bile Acids: regulation of Synthesis.
    Journal of Lipid Research, 2009
    Co-Authors: John Y. L. Chiang
    Abstract:

    Bile Acids are physiological detergents that generate Bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile Acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of Bile Acids exerts important physiological functions not only in feedback inhibition of Bile Acid Synthesis but also in control of whole-body lipid homeostasis. In the liver, Bile Acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4α and results in inhibiting transcription of the critical regulatory gene in Bile Acid Synthesis, cholesterol 7α-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit Bile Acid Synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile Acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile Acids and Bile Acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome.

Susan Kennedy - One of the best experts on this subject based on the ideXlab platform.

Kenneth D R Setchell - One of the best experts on this subject based on the ideXlab platform.

  • open label phase 3 continuation study of cholic Acid in patients with inborn errors of Bile Acid Synthesis
    Journal of Pediatric Gastroenterology and Nutrition, 2020
    Co-Authors: James E Heubi, Kenneth D R Setchell
    Abstract:

    BACKGROUND In patients with Bile Acid Synthesis disorders (BASD), impairment in the primary Bile Acid synthetic pathway leads to reduced primary Bile Acids, upregulated Synthesis of cholesterol, and production and accumulation of hepatotoxic atypical Bile Acids. Primary Bile Acid therapy downregulates Bile Acid Synthesis, reduces the production of hepatotoxic intermediates, and produces a functional Bile Acid pool fostering normal liver function. METHODS This phase 3, open-label, single-arm study included patients with BASD who had received cholic Acid (10-15 mg · kg · day) as part of a previous study, or were newly diagnosed. Efficacy assessments included urinary atypical Bile Acids; serum liver chemistries; body weight and height. Efficacy analyses compared baseline with worst postbaseline response (primary) or best postbaseline response (sensitivity). Treatment-emergent adverse events (TEAEs) were summarized. RESULTS Of 53 total patients (single enzyme defects, n = 41; Zellweger spectrum disorders, n = 12), 22 (42%) were treatment-naive, and 31 (58%) were on cholic Acid from a previous study. Mean age at diagnosis was 55 months, and at present study, baseline was 9 years. Using baseline-to-best postbaseline analyses, statistically significant improvements in urinary Bile Acids (P = 0.003), height (P < 0.001), and body weight (P < 0.001) were observed. Serum alanine aminotransferase and aspartate aminotransferase levels tended to decrease from baseline in treatment-naive patients following cholic Acid treatment and remained stable in previously treated patients. Treatment-naive patients improved in all baseline-to-best postbaseline analyses. The most common TEAE was upper respiratory tract infection (17%). CONCLUSION Oral cholic Acid provides a safe and efficacious short- and long-term therapy for patients with BASD.

  • δ4 3 oxosteroid 5β reductase deficiency responses to oral Bile Acid therapy and long term outcomes
    World Journal of Gastroenterology, 2019
    Co-Authors: Meihong Zhang, Jingyu Gong, Kenneth D R Setchell, Yi Lu, Jing Zhao, Jianshe Wang
    Abstract:

    BACKGROUND Disorders of primary Bile Acid Synthesis may be life-threatening if undiagnosed, or not treated with primary Bile Acid replacement therapy. To date, there are few reports on the management and follow-up of patients with Δ4-3-oxosteroid 5β-reductase (AKR1D1) deficiency. We hypothesized that a retrospective analysis of the responses to oral Bile Acid replacement therapy with chenodeoxycholic Acid (CDCA) in patients with this Bile Acid Synthesis disorder will increase our understanding of the disease progression and permit evaluation of this treatment regimen as an alternative to the Food and Drug Administration (FDA) approved drug cholic Acid, which is currently unavailable in China.

  • oral cholic Acid is efficacious and well tolerated in patients with Bile Acid Synthesis and zellweger spectrum disorders
    Journal of Pediatric Gastroenterology and Nutrition, 2017
    Co-Authors: James E Heubi, Kevin E Bove, Kenneth D R Setchell
    Abstract:

    OBJECTIVES Patients with Bile Acid Synthesis disorders (BASDs) due to single enzyme defects (SEDs) or Zellweger spectrum disorders (ZSDs) accumulate hepatotoxic atypical Bile Acids resulting in potentially fatal progressive liver disease. We evaluated the efficacy and safety of oral cholic Acid in patients with BASD. METHODS In this phase 3, open-label, single-arm, nonrandomized, noncomparative study conducted over 18 years, patients were administered cholic Acid orally 10 to 15 mg · kg · day. The primary efficacy variables were changes from pre- to post-treatment in atypical urinary Bile Acids, liver chemistries (serum aspartate aminotransferase, alanine aminotransferase), and height and weight. Additional efficacy variables included changes in serum bilirubin and liver histology. RESULTS Of the 85 enrolled patients (63 with SED and 22 with ZSD), 79 received at least 1 dose of study medication; 70 patients (50 with SED and 20 with ZSD) were included in the modified intent-to-treat dataset. Cholic Acid significantly improved urine Bile Acid metabolite scores (P < 0.0001) and serum aspartate aminotransferase and alanine aminotransferase (P < 0.0001) in patients with SED and ZSD. Cholic Acid also improved height and weight percentiles in both groups, but only the change in weight was significant (P < 0.05). Serum direct bilirubin decreased significantly post-treatment (P < 0.001) in the intent-to-treat population, and liver biopsies showed either stable findings or histologic improvement in all parameters except bridging fibrosis. The overall safety profile of cholic Acid was favorable, with no study drug-related serious adverse events or drug-related deaths reported. CONCLUSIONS Oral cholic Acid is a safe, efficacious, and well-tolerated treatment for BASD due to SED and ZSD.

  • oral cholic Acid for hereditary defects of primary Bile Acid Synthesis a safe and effective long term therapy
    Gastroenterology, 2009
    Co-Authors: Emmanuel Gonzales, Kenneth D R Setchell, James E Heubi, Marie Gerhardt, Monique Fabre, Anne Spraul, Isabelle Vincent, Olivier Bernard, Emmanuel Jacquemin
    Abstract:

    Background & Aims Oral Bile Acid replacement has been shown to be an effective therapy in primary Bile Acid Synthesis defects, but to date there have been no reports of the long-term effects of this therapy. The aim of the study was to evaluate the long-term effectiveness and safety of cholic Acid (CA) therapy. Methods Fifteen patients with either 3β-hydroxy-Δ 5 -C 27 -steroid oxidoreductase (3β-HSD) (n = 13) or Δ 4 -3-oxosteroid 5β-reductase (Δ 4 -3-oxo-R) (n = 2) deficiency confirmed by mass spectrometry and gene sequencing received oral CA and were followed up prospectively. Results CA therapy was started at a median age of 3.9 years (range, 0.3–13.1 years). The median follow-up with treatment was 12.4 years (range, 5.6–15 years). The mean daily dose of CA was initially 13 mg/kg and was 6 mg/kg at last evaluation. During CA therapy, physical examination findings, laboratory test results, and findings on sonography normalized. Mass spectrometry analysis of urine showed that excretion of the atypical metabolites was reduced by 500-fold and 30-fold in 3β-HSD and Δ 4 -3-oxo-R deficiency, respectively, and total urinary Bile Acid excretion decreased dramatically. Liver biopsies performed in 14 patients after at least 5 years of CA therapy showed marked improvement, especially in patients with the 3β-HSD deficiency. CA was well tolerated with all children developing normally, including 2 women having 4 normal pregnancies during treatment. Conclusions Oral CA therapy is a safe and effective long-term treatment of the most common primary Bile Acid Synthesis defects.

  • identification of a new inborn error in Bile Acid Synthesis mutation of the oxysterol 7alpha hydroxylase gene causes severe neonatal liver disease
    Journal of Clinical Investigation, 1998
    Co-Authors: Kenneth D R Setchell, Margrit Schwarz, Ronald J Sokol, Nancy C Oconnell, Erik G Lund, Daphne L Davis, Richard Lathe, Henry R Thompson, Weslie R Tyson, David W. Russell
    Abstract:

    We describe a metabolic defect in Bile Acid Synthesis involving a deficiency in 7alpha-hydroxylation due to a mutation in the gene for the microsomal oxysterol 7alpha-hydroxylase enzyme, active in the Acidic pathway for Bile Acid Synthesis. The defect, identified in a 10-wk-old boy presenting with severe cholestasis, cirrhosis, and liver synthetic failure, was established by fast atom bombardment ionization-mass spectrometry, which revealed elevated urinary Bile Acid excretion, a mass spectrum with intense ions at m/z 453 and m/z 510 corresponding to sulfate and glycosulfate conjugates of unsaturated monohydroxy-cholenoic Acids, and an absence of primary Bile Acids. Gas chromatography-mass spectrometric analysis confirmed the major products of hepatic Synthesis to be 3beta-hydroxy-5-cholenoic and 3beta-hydroxy-5-cholestenoic Acids, which accounted for 96% of the total serum Bile Acids. Levels of 27-hydroxycholesterol were > 4,500 times normal. The biochemical findings were consistent with a deficiency in 7alpha-hydroxylation, leading to the accumulation of hepatotoxic unsaturated monohydroxy Bile Acids. Hepatic microsomal oxysterol 7alpha-hydroxylase activity was undetectable in the patient. Gene analysis revealed a cytosine to thymidine transition mutation in exon 5 that converts an arginine codon at position 388 to a stop codon. The truncated protein was inactive when expressed in 293 cells. These findings indicate the quantitative importance of the Acidic pathway in early life in humans and define a further inborn error in Bile Acid Synthesis as a metabolic cause of severe cholestatic liver disease.

Thomas A Kerr - One of the best experts on this subject based on the ideXlab platform.

Hans M.g. Princen - One of the best experts on this subject based on the ideXlab platform.

  • fibrates suppress Bile Acid Synthesis via peroxisome proliferator activated receptor α mediated downregulation of cholesterol 7α hydroxylase and sterol 27 hydroxylase expression
    Arteriosclerosis Thrombosis and Vascular Biology, 2001
    Co-Authors: S M Post, Bart Staels, Helene Duez, Philippe Gervois, Folkert Kuipers, Hans M.g. Princen
    Abstract:

    Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases Bile Acid excretion, leading to an increased incidence of cholesterol gallstones. In this study, we investigated the effect of fibrates on Bile Acid Synthesis. Ciprofibrate and the PPARalpha agonist Wy14,643 decreased Bile Acid Synthesis in cultured rat hepatocytes and suppressed cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase activities, paralleled by a similar reduction of the respective mRNAs. Treatment of rats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7alpha-hydroxylase enzyme activity and mRNA. The functional involvement of PPARalpha in the suppression of both enzymes was proven with the use of PPARalpha-null mice. In wild-type mice, ciprofibrate reduced cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA of both enzymes is regulated transcriptionally and posttranscriptionally, respectively, resulting in a decline in the output of fecal Bile Acids (-45%) and a 3-fold increase in fecal cholesterol secretion. These effects were completely abolished in PPARalpha-null mice. A decreased Bile Acid production by PPARalpha-mediated downregulation of cholesterol 7alpha-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.

  • insulin suppresses Bile Acid Synthesis in cultured rat hepatocytes by down regulation of cholesterol 7α hydroxylase and sterol 27 hydroxylase gene transcription
    Hepatology, 1995
    Co-Authors: J Twisk, M.f.m. Hoekman, Eline M Lehmann, P Meijer, Willem H Mager, Hans M.g. Princen
    Abstract:

    Evidence from in vivo studies indicates that the Bile Acid pool and Bile Acid excretion are increased in humans with diabetes mellitus and in experimental diabetic animals, and that both parameters return to normal levels after administration of insulin. To investigate the biochemical background of these changes, the effects of insulin on Bile Acid Synthesis and cholesterol 7α-hydroxylase and sterel 27-hydroxylase, two key enzymes in routing of cholesterol toward Bile Acids, were studied in cultured rat hepatocytes. Mass production of Bile Acids was dose dependently diminished, showing significant reduction (-33% to -53%) at physiological concentrations of the hormone (1.4 to 14 nmol/L) and a maximal decrease at 140 nmol/L (- 65%). The decrease of Bile Acid Synthesis correlated well with the suppression of cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity. The enzyme activity for cholesterol 7α-hydroxylase, examined in more detail, was dose dependently diminished on incubation of hepatocytes with various concentrations of insulin, reaching maximal reduction at 14 nmol/L of insulin. Maximal decrease of the enzyme activity was seen after 8 hours of incubation (-70%). Insulin strongly reduced the rise in cholesterol 7α-hydroxylase activity induced by incubation with dexamethasone. Sterol 27- hydroxylase activity was inhibited up to -58% after 24 hours of incubation with 140 nmol/L insulin. To study the mechanism of suppression of cholesterol 7α-hydroxylase and sterol 27-hydroxylase activity, the effects of insulin on their respective levels of messenger RNA (mRNA) and gene transcription were assessed. The decrease in enzyme activities could be explained by a concomitant reduction in the cholesterol 7α-hydroxylase (-76%) and sterol 27-hydroxylase (-62%) mRNA level. Transcriptional activity, as assessed by nuclear runoff assays, was decreased to the same extent, i.e., -60% for cholesterol 7α-hydroxylase and -75% for sterol 27-hydroxylase. Transient expression experiments using a construct containing the proximal 348 basepairs of the cholesterol 7α-hydroxylase promoter fused to the chloramphenicol acetyltransferase (CAT) gene (-348Rcat) showed a significant reduction of transcriptional activity (-64%) with insulin, indicating that a sequence important for an insulin-induced transcriptional response is located within the first 348 basepairs, preceding the transcription start of the cholesterol 7α-hydroxylase promoter. We conclude that physiological concentrations of insulin suppress Bile Acid Synthesis by downregulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase gene transcription, and that this effect is mediated through a direct action of the hormone on the hepatocyte. These results may provide an explanation for the increased Bile Acid pool and excretion as found in humans with untreated diabetes mellitus and in experimental animals with insulin deficiency. Chemicals/CAS: cholesterol 7alpha monooxygenase, 9037-53-0; insulin, 9004-10-8; oxygenase, 9037-29-0, 9046-59-7; sterol 27 hydroxylase, 134712-57-5; Bile Acids and Salts; Chloramphenicol O-Acetyltransferase, EC 2.3.1.28; Cholesterol 7-alpha-Hydroxylase, EC 1.14.13.17; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; Insulin, 11061-68-0; Membrane Glycoproteins; nuclear pore glycoprotein gp210; Nuclear Proteins; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-