Glucose-6-Phosphate Regulates Hepatic Bile Acid Synthesis in Mice
Autor: | Yu Lei, Henkjan J. Verkade, Vincent W. Bloks, Gilles Mithieux, Justina C. Wolters, Folkert Kuipers, Fabienne Rajas, Joanne A Hoogerland, Maaike H. Oosterveer, Jan Albert Kuivenhoven, Rebecca A. Haeusler, Niels L. Mulder, Aycha Bleeker, Jan Freark de Boer, Theo H. van Dijk, Trijnie Bos |
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Přispěvatelé: | Academic Medical Center, Department of Pediatrics and Laboratory Medicine [Groningen, The Netherlands], University Medical Center Groningen [Groningen] (UMCG), Nutrition, diabète et cerveau (NUDICE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Pathology and Cell Biology [New York, NY, USA], Columbia University Irving Medical Center (CUIMC), Supported by an unrestricted research grant from DSM Nutritional Products (Kaiseraugst, Switzerland). M.H.O. is the recipient of a VIDI grant from the Dutch Scientific Organization and holds a Rosalind Franklin Fellowship from the University of Groningen. R.A.H. is supported by R01HL125649 from the National Institutes of Health. F.K. is supported by CardioVasculair Onderzoek Nederland (CVON2012-03)., Di Carlo, Marie-Ange, Nutrition, diabète et cerveau, Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM) |
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
Male
0301 basic medicine medicine.drug_class Glucose-6-Phosphate Bile Acids and Salts Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Liver Biology/Pathobiology medicine Animals Humans Steroid 12-alpha-Hydroxylase [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Intestinal Mucosa Carbohydrate-responsive element-binding protein Hepatology Bile acid Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Cholesterol Lipid metabolism Original Articles Sterol Mice Inbred C57BL 030104 developmental biology Liver Biochemistry Glucose 6-phosphate chemistry Intestinal cholesterol absorption Original Article [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] 030211 gastroenterology & hepatology CYP8B1 |
Zdroj: | Hepatology (Baltimore, Md.), 70(6), 2171-2184. John Wiley and Sons Ltd Hepatology Hepatology, Wiley-Blackwell, 2019, ⟨10.1002/hep.30778⟩ Hepatology, 70(6), 2171-2184. Wiley Hepatology (Baltimore, Md.) |
ISSN: | 0270-9139 1527-3350 |
Popis: | It is well-established that, besides facilitating lipid absorption, bile acids act as signaling molecules that modulate glucose and lipid metabolism. Bile acid metabolism, in turn, is controlled by several nutrient-sensitive transcription factors. Altered intrahepatic glucose signaling in type 2 diabetes associates with perturbed bile acid synthesis. However, an independent role of glucose in regulation of bile acid metabolism has as yet not been established. We aimed to characterize the regulatory role of the primary intracellular metabolite of glucose, glucose-6-phosphate (G6P), on bile acid metabolism. Hepatic gene expression patterns and bile acid composition were analyzed in mice that accumulate G6P in the liver, i.e., liver-specific glucose-6-phosphatase knockout (L-G6pc-/- ) mice, and mice treated with a pharmacological inhibitor of the G6P-transporter. Hepatic G6P accumulation induces Cyp8b1 expression, which is mediated by the major glucose-sensitive transcription factor Carbohydrate Response Element Binding Protein (ChREBP). Activation of the G6P-ChREBP-CYP8B1 axis increases the relative abundance of cholic acid-derived bile acids and induces physiologically relevant shifts in bile composition. The G6P-ChREBP-dependent change in bile acid hydrophobicity associates with elevated plasma campesterol/cholesterol ratio and reduced fecal neutral sterol loss, compatible with enhanced intestinal cholesterol absorption. CONCLUSION: We report that G6P, the primary intracellular metabolite of glucose, controls hepatic bile acid synthesis. Our work identifies hepatic G6P-ChREBP-CYP8B1 signaling as a regulatory axis in control of bile acid and cholesterol metabolism. This article is protected by copyright. All rights reserved. |
Databáze: | OpenAIRE |
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