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Cited by 57Liver Diseases and ImmunityDrug Transport and Resistance MechanismsDrug-Induced Hepatotoxicity and Protection

Fenofibrate Improves Liver Function and Reduces the Toxicity of the Bile Acid Pool in Patients With Primary Biliary Cholangitis and Primary Sclerosing Cholangitis Who Are Partial Responders to Ursodiol

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Ghonem, Nisanne S., Auclair, Adam M., Hemme, Christopher L., Gallucci, Gina M., de la Rosa Rodriguez, Randolph, Boyer, James L., Assis, David N.·2020·Clinical Pharmacology & Therapeutics
DOI 10.1002/cpt.1930PMC PMC7886378
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Abstract

Cholestatic liver diseases result in the hepatic retention of bile acids, causing subsequent liver toxicity. Peroxisome proliferator‐activated receptor alpha (PPARα) regulates bile acid metabolism. In this retrospective observational study, we assessed the effects of fenofibrate (a PPARα agonist) therapy on bile acid metabolism when given to patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) who have had an incomplete response to Ursodiol monotherapy. When fenofibrate was added to Ursodiol therapy there was a significant reduction and in some cases normalization of serum alkaline phosphatase, alanine aminotransferase, and aspartate aminotransferase abnormalities, as well as pro‐inflammatory cytokines. Combination fenofibrate treatment also reduced 7α‐hydroxy‐4‐cholesten‐3‐one (C4), the bile acid precursor, as well as total, primary, and conjugated bile acids. In addition, principal components analysis and heatmap analysis show that bile acid metabolites trended closer to that of healthy control subjects. These favorable effects of fenofibrate on bile acid metabolism may contribute to its beneficial clinical effects in patients with PBC and PSC experiencing a subtherapeutic response to Ursodiol monotherapy.

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Research works printed but not linked: 27

  1. [1]Boyer JL Bile formation and secretion. Compr Physiol 3, 1035– 78 (2013). 23897680 PMC4091928
  2. [2]Cai SY Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight 2, e90780 (2017). 28289714 PMC5333973
  3. [3]Leuschner M Characterisation of patients with primary biliary cirrhosis responding to long term ursodeoxycholic acid treatment. Gut 46, 121– 6 (2000). 10601067 PMC1727784
  4. [4]Bowlus CL Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: clinical utility and patient selection. Hepat Med 8, 89– 95 (2016). 27621676 PMC5012622
  5. [7]Issemann I & Green S Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347, 645– 50 (1990). 2129546
  6. [8]Ghonem NS & Boyer JL Fibrates as adjuvant therapy for chronic cholestatic liver disease: its time has come. Hepatology 57, 1691– 3 (2013). 23174993 PMC4048949
  7. [9]Lemoinne S Primary sclerosing cholangitis response to the combination of fibrates with ursodeoxycholic acid: French-Spanish experience. Clin Res Hepatol Gastroenterol 42, 521– 8 (2018). 30100231
  8. [10]Trottier J Metabolomic profiling of 17 bile acids in serum from patients with primary biliary cirrhosis and primary sclerosing cholangitis: a pilot study. Dig Liver Dis 44, 303– 10 (2012). 22169272
  9. [11]Zweers SJ Elevated interleukin-8 in bile of patients with primary sclerosing cholangitis. Liver Int 36, 1370– 7 (2016). 26866350
  10. [12]Attili AF, Angelico M, Cantafora A, Alvaro D & Capocaccia L Bile acid-induced liver toxicity: relation to the hydrophobic-hydrophilic balance of bile acids. Med Hypotheses 19, 57– 69 (1986). 2871479
  11. [15]Solaas K, Kase BF, Pham V, Bamberg K, Hunt MC & Alexson SE Differential regulation of cytosolic and peroxisomal bile acid amidation by PPAR alpha activation favors the formation of unconjugated bile acids. J Lipid Res 45, 1051– 60 (2004). 15026425
  12. [16]Trottier J Profiling serum bile acid glucuronides in humans: gender divergences, genetic determinants, and response to fenofibrate. Clin Pharmacol Ther 94, 533– 43 (2013). 23756370 PMC4844538
  13. [17]Fang HL, Strom SC, Cai H, Falany CN, Kocarek TA & Runge-Morris M Regulation of human hepatic hydroxysteroid sulfotransferase gene expression by the peroxisome proliferator-activated receptor alpha transcription factor. Molecular pharmacology 67, 1257– 67 (2005). 15635043
  14. [18]Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E & Fruchart JC Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98, 2088– 93 (1998). 9808609
  15. [19]Willson TM, Brown PJ, Sternbach DD & Henke BR The PPARs: from orphan receptors to drug discovery. J Med Chem 43, 527– 50 (2000). 10691680
  16. [20]Girroir EE, Hollingshead HE, He P, Zhu B, Perdew GH & Peters JM Quantitative expression patterns of peroxisome proliferator-activated receptor-beta/delta (PPARbeta/delta) protein in mice. Biochem Biophys Res Commun 371, 456– 61 (2008). 18442472 PMC2586836
  17. [21]Barish GD, Narkar VA & Evans RM PPAR delta: a dagger in the heart of the metabolic syndrome. J Clin Invest 116, 590– 7 (2006). 16511591 PMC1386117
  18. [22]Mizuno S Prospective study of bezafibrate for the treatment of primary sclerosing cholangitis. J Hepatobiliary Pancreat Sci 22, 766– 70 (2015). 26173026
  19. [23]El-Sisi A, Hegazy S & El-Khateeb E Effects of three different fibrates on intrahepatic cholestasis experimentally induced in rats. PPAR Res 2013, 781348 (2013). 23997763 PMC3753769
  20. [24]Jones D Seladelpar (MBX-8025), a selective PPAR-delta agonist, in patients with primary biliary cholangitis with an inadequate response to ursodeoxycholic acid: a double-blind, randomised, placebo-controlled, phase 2, proof-of-concept study. Lancet Gastroenterol Hepatol 2, 716– 26 (2017). 28818518
  21. [25]Marrapodi M & Chiang JY Peroxisome proliferator-activated receptor alpha (PPARalpha) and agonist inhibit cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. J Lipid Res 41, 514– 20 (2000). 10744771
  22. [26]Bertolotti M Effects of different phenotypes of hyperlipoproteinemia and of treatment with fibric acid derivatives on the rates of cholesterol 7 alpha-hydroxylation in humans. Arterioscler Thromb Vasc Biol 15, 1064– 9 (1995). 7627697
  23. [27]Kok T Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. Biochem J 369, 539– 47 (2003). 12381268 PMC1223107
  24. [28]Lee MY Peroxisome proliferator-activated receptor delta agonist attenuates hepatic steatosis by anti-inflammatory mechanism. Exp Mol Med 44, 578– 85 (2012). 22824914 PMC3490079
  25. [29]Delerive P, Gervois P, Fruchart JC & Staels B Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem 275, 36703– 7 (2000). 10980195
  26. [30]Dai M Inhibition of JNK signalling mediates PPARalpha-dependent protection against intrahepatic cholestasis by fenofibrate. Br J Pharmacol 174, 3000– 17 (2017). 28646549 PMC5573431
  27. [31]Cheung AC Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther 43, 283– 93 (2016). 26559762

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Authors
Ghonem, N. S., Auclair, A. M., Hemme, C. L., Gallucci, G. M., de la Rosa Rodriguez, R., Boyer, J. L., & Assis, D. N.
Affiliations
  • University of Rhode Island (US)
  • Liver Center Yale University School of Medicine New Haven Connecticut USA
  • Yale University (US)
Corresponding author
Ghonem, Nisanne S.
ORCID
Venue
Clinical Pharmacology & Therapeutics
Publisher
Wiley
Published
2020-07-17
Volume
108
Issue
6
Pages
1213-1223
ISSN
  • 0009-9236 (ISSN-L)
  • 1532-6535
DOI
10.1002/cpt.1930
PMC
PMC7886378
OpenAlex
W3029615956
Cited by
57
References
4
Citations by year
2026: 8 · 2025: 7 · 2024: 15 · 2023: 9 · 2022: 9 · 2021: 8 · 2020: 1
FWCI
3.97
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Clinical Pharmacology & Therapeutics (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Journal of Media Literacy Education (submittedVersion, cc-by)
Funders
  • National Institutes of Health (UL1TR001863)
  • National Institute of General Medical Sciences (P20GM103430)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK034989)
  • National Center for Advancing Translational Sciences
Topics
  • Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords
fenofibrate, primary biliary cirrhosis, primary sclerosing cholangitis, ursodeoxycholic acid, bile acid metabolism, PPARα agonist, cholestatic liver disease, liver function, 7α-hydroxy-4-cholesten-3-one, inflammatory cytokines, combination therapy
MeSH terms
Adult, Aged, Bile Acids and Salts, Drug Therapy, Combination, Female, Humans, Liver, Liver Cirrhosis, Biliary, Liver Function Tests, Male, Middle Aged, Fenofibrate, Retrospective Studies, Ursodeoxycholic Acid, Cholangitis, Sclerosing, Biomarkers, Cytokines, Treatment Outcome, Inflammation Mediators, Principal Component Analysis, PPAR alpha, Young Adult

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