Farnesoid X Receptor Inhibits the Transcriptional Activity of Carbohydrate Response Element Binding Protein in Human Hepatocytes

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2013 Mar 27

PMID 23530060

Citations 67

Authors

Sandrine Caron

Carolina Huaman Samanez

Helene Dehondt

Maheul Ploton

Olivier Briand

Fleur Lien

Emilie Dorchies

Julie Dumont

Catherine Postic

Bertrand Cariou

Philippe Lefebvre

Bart Staels

Affiliations

Soon will be listed here.

Abstract

The glucose-activated transcription factor carbohydrate response element binding protein (ChREBP) induces the expression of hepatic glycolytic and lipogenic genes. The farnesoid X receptor (FXR) is a nuclear bile acid receptor controlling bile acid, lipid, and glucose homeostasis. FXR negatively regulates hepatic glycolysis and lipogenesis in mouse liver. The aim of this study was to determine whether FXR regulates the transcriptional activity of ChREBP in human hepatocytes and to unravel the underlying molecular mechanisms. Agonist-activated FXR inhibits glucose-induced transcription of several glycolytic genes, including the liver-type pyruvate kinase gene (L-PK), in the immortalized human hepatocyte (IHH) and HepaRG cell lines. This inhibition requires the L4L3 region of the L-PK promoter, known to bind the transcription factors ChREBP and hepatocyte nuclear factor 4α (HNF4α). FXR interacts directly with ChREBP and HNF4α proteins. Analysis of the protein complex bound to the L4L3 region reveals the presence of ChREBP, HNF4α, FXR, and the transcriptional coactivators p300 and CBP at high glucose concentrations. FXR activation does not affect either FXR or HNF4α binding to the L4L3 region but does result in the concomitant release of ChREBP, p300, and CBP and in the recruitment of the transcriptional corepressor SMRT. Thus, FXR transrepresses the expression of genes involved in glycolysis in human hepatocytes.

Citing Articles

Disentangling Organ-Specific Roles of Farnesoid X Receptor in Bile Acid and Glucolipid Metabolism.

Li T, Fu C, Tang Z, Li C, Hua D, Liu B Liver Int. 2025; 45(4):e70027.

PMID: 40052709 PMC: 11887529. DOI: 10.1111/liv.70027.

Potential therapeutic strategies for MASH: from preclinical to clinical development.

Xie Z, Li Y, Cheng L, Huang Y, Rao W, Shi H Life Metab. 2025; 3(5):loae029.

PMID: 39872142 PMC: 11749562. DOI: 10.1093/lifemeta/loae029.

Pathophysiological Relationship between Type 2 Diabetes Mellitus and Metabolic Dysfunction-Associated Steatotic Liver Disease: Novel Therapeutic Approaches.

Ferdous S, Ferrell J Int J Mol Sci. 2024; 25(16).

PMID: 39201418 PMC: 11354927. DOI: 10.3390/ijms25168731.

Normoglycemia and physiological cortisone level maintain glucose homeostasis in a pancreas-liver microphysiological system.

Rigal S, Casas B, Kanebratt K, Wennberg Huldt C, Magnusson L, Mullers E Commun Biol. 2024; 7(1):877.

PMID: 39025915 PMC: 11258270. DOI: 10.1038/s42003-024-06514-w.

Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development.

Li T, Chiang J Pharmacol Rev. 2024; 76(6):1221-1253.

PMID: 38977324 PMC: 11549937. DOI: 10.1124/pharmrev.124.000978.

References

Yamashita H, Takenoshita M, Sakurai M, Bruick R, Henzel W, Shillinglaw W . A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc Natl Acad Sci U S A. 2001; 98(16):9116-21. PMC: 55382. DOI: 10.1073/pnas.161284298. View

Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K . Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein. Proc Natl Acad Sci U S A. 2001; 98(24):13710-5. PMC: 61106. DOI: 10.1073/pnas.231370798. View

Gripon P, Rumin S, Urban S, Le Seyec J, Glaise D, Cannie I . Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci U S A. 2002; 99(24):15655-60. PMC: 137772. DOI: 10.1073/pnas.232137699. View

Guinez C, Filhoulaud G, Rayah-Benhamed F, Marmier S, Dubuquoy C, Dentin R . O-GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver. Diabetes. 2011; 60(5):1399-413. PMC: 3292313. DOI: 10.2337/db10-0452. View

Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, Dentin R . Salt-inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP-dependent hepatic steatosis in mice. J Clin Invest. 2010; 120(12):4316-31. PMC: 2993582. DOI: 10.1172/JCI41624. View

Watson P, Fairall L, Schwabe J . Nuclear hormone receptor co-repressors: structure and function. Mol Cell Endocrinol. 2011; 348(2):440-9. PMC: 3315023. DOI: 10.1016/j.mce.2011.08.033. View

Wang H, Chen J, HOLLISTER K, Sowers L, Forman B . Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell. 1999; 3(5):543-53. DOI: 10.1016/s1097-2765(00)80348-2. View

Gonzalez F . Regulation of hepatocyte nuclear factor 4 alpha-mediated transcription. Drug Metab Pharmacokinet. 2008; 23(1):2-7. DOI: 10.2133/dmpk.23.2. View

Parviz F, Matullo C, Garrison W, Savatski L, Adamson J, Ning G . Hepatocyte nuclear factor 4alpha controls the development of a hepatic epithelium and liver morphogenesis. Nat Genet. 2003; 34(3):292-6. DOI: 10.1038/ng1175. View

10.

Schippers I, Moshage H, Roelofsen H, Muller M, Heymans H, Ruiters M . Immortalized human hepatocytes as a tool for the study of hepatocytic (de-)differentiation. Cell Biol Toxicol. 1997; 13(4-5):375-86. DOI: 10.1023/a:1007404028681. View

11.

Bouche C, Serdy S, Kahn C, Goldfine A . The cellular fate of glucose and its relevance in type 2 diabetes. Endocr Rev. 2004; 25(5):807-30. DOI: 10.1210/er.2003-0026. View

12.

Dentin R, Tomas-Cobos L, Foufelle F, Leopold J, Girard J, Postic C . Glucose 6-phosphate, rather than xylulose 5-phosphate, is required for the activation of ChREBP in response to glucose in the liver. J Hepatol. 2011; 56(1):199-209. DOI: 10.1016/j.jhep.2011.07.019. View

13.

Diaz-Moralli S, Ramos-Montoya A, Marin S, Fernandez-Alvarez A, Casado M, Cascante M . Target metabolomics revealed complementary roles of hexose- and pentose-phosphates in the regulation of carbohydrate-dependent gene expression. Am J Physiol Endocrinol Metab. 2012; 303(2):E234-42. DOI: 10.1152/ajpendo.00675.2011. View

14.

Huaman Samanez C, Caron S, Briand O, Dehondt H, Duplan I, Kuipers F . The human hepatocyte cell lines IHH and HepaRG: models to study glucose, lipid and lipoprotein metabolism. Arch Physiol Biochem. 2012; 118(3):102-11. DOI: 10.3109/13813455.2012.683442. View

15.

Jeong Y, Kim D, Lee Y, Kim H, Han J, Im S . Integrated expression profiling and genome-wide analysis of ChREBP targets reveals the dual role for ChREBP in glucose-regulated gene expression. PLoS One. 2011; 6(7):e22544. PMC: 3141076. DOI: 10.1371/journal.pone.0022544. View

16.

Girard J, Ferre P, Foufelle F . Mechanisms by which carbohydrates regulate expression of genes for glycolytic and lipogenic enzymes. Annu Rev Nutr. 1997; 17:325-52. DOI: 10.1146/annurev.nutr.17.1.325. View

17.

Pascual G, Fong A, Ogawa S, Gamliel A, Li A, Perissi V . A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature. 2005; 437(7059):759-63. PMC: 1464798. DOI: 10.1038/nature03988. View

18.

Makishima M, Okamoto A, REPA J, Tu H, Learned R, Luk A . Identification of a nuclear receptor for bile acids. Science. 1999; 284(5418):1362-5. DOI: 10.1126/science.284.5418.1362. View

19.

Li M, Yang X . A Retrospective on Nuclear Receptor Regulation of Inflammation: Lessons from GR and PPARs. PPAR Res. 2011; 2011:742785. PMC: 3175381. DOI: 10.1155/2011/742785. View

20.

Cariou B, van Harmelen K, Duran-Sandoval D, van Dijk T, Grefhorst A, Abdelkarim M . The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem. 2006; 281(16):11039-49. DOI: 10.1074/jbc.M510258200. View