Fibrates and cholestasis

Ghonem, Nisanne S.; Assis, David N.; Boyer, James L.

doi:10.1002/hep.27744

Cited by 318Drug Transport and Resistance MechanismsLiver Diseases and ImmunityPeroxisome Proliferator-Activated Receptors

Fibrates and cholestasis

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Ghonem, Nisanne S., Assis, David N., Boyer, James L.·2015·Hepatology

DOI 10.1002/hep.27744PMC PMC4515188

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Abstract

Cholestasis, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), results from an impairment or disruption of bile production and causes intracellular retention of toxic bile constituents, including bile salts. If left untreated, cholestasis leads to liver fibrosis and cirrhosis, which eventually results in liver failure and the need for liver transplantation. Currently, the only therapeutic option available for these patients is ursodeoxycholic acid (UDCA), which slows the progression of PBC, particularly in stage I and II of the disease. However, some patients have an incomplete response to UDCA therapy, whereas other, more advanced cases often remain unresponsive. For PSC, UDCA therapy does not improve survival, and recommendations for its use remain controversial. These considerations emphasize the need for alternative therapies. Hepatic transporters, located along basolateral (sinusoidal) and apical (canalicular) membranes of hepatocytes, are integral determinants of bile formation and secretion. Nuclear receptors (NRs) are critically involved in the regulation of these hepatic transporters and are natural targets for therapy of cholestatic liver diseases. One of these NRs is peroxisome proliferator‐activated receptor alpha (PPARα), which plays a central role in maintaining cholesterol, lipid, and bile acid homeostasis by regulating genes responsible for bile acid synthesis and transport in humans, including cytochrome P450 (CYP) isoform 7A1 (CYP7A1), CYP27A1, CYP8B1, uridine 5'‐diphospho‐glucuronosyltransferase 1A1, 1A3, 1A4, 1A6, hydroxysteroid sulfotransferase enzyme 2A1, multidrug resistance protein 3, and apical sodium‐dependent bile salt transporter. Expression of many of these genes is altered in cholestatic liver diseases, but few have been extensively studied or had the mechanism of PPARα effect identified. In this review, we examine what is known about these mechanisms and consider the rationale for the use of PPARα ligand therapy, such as fenofibrate, in various cholestatic liver disorders. (H epatology 2015;62:635–643

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Fibrates exert potent anticholestatic effects through the variable activation of peroxisome proliferator-activated receptors (PPAR), in addition to downregulation of several pathways leading to bile acid synthesis.
“Fibrates exert potent anticholestatic effects through the variable activation of peroxisome proliferator-activated receptors (PPAR), in addition to downregulation of several pathways leading to bile acid synthesis.162”
From The British Society of Gastroenterology/UK-PBC primary biliary cholangitis treatment and management guidelines (2018) · cites this paper as [162]
Section II describes fibrates’ differing activation of PPAR subtypes, and Section III reports PPARα-mediated inhibition of two bile-acid-synthesis enzymes. Section VI reports improvements in cholestasis with bezafibrate and fenofibrate, but says clofibrate and gemfibrozil have not been studied in human cholestatic disorders. Thus, the claim’s unqualified assertion that fibrates exert potent anticholestatic effects extends beyond the clinical evidence reviewed. Page numbers were not provided in our copy. (LLM, conf=0.84)
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MECHANISMS OF PPAR-ALPHA TARGETED THERAPY IN CHOLESTASIS: TRANSLATIONAL STUDIES
Gallucci, G. M. (2023) · Digital Commons - URI (University of Rhode Island)

Authors: Ghonem, N. S., Assis, D. N., & Boyer, J. L.
Affiliations: Massachusetts College of Pharmacy and Health Sciences (US)
Yale University (US)
Corresponding author: Boyer, James L.
ORCID: Ghonem, Nisanne S.
Assis, David N.
Boyer, James L.
Venue: Hepatology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2015-03-23
Volume: 62
Issue: 2
Pages: 635-643
ISSN: 0270-9139 (ISSN-L)
1527-3350
DOI: 10.1002/hep.27744
PMC: PMC4515188
OpenAlex: W1726014254
Cited by: 317
References: 86
Citations by year: 2026: 22 · 2025: 25 · 2024: 31 · 2023: 40 · 2022: 39 · 2021: 33 · 2020: 24 · 2019: 25 · 2018: 26 · 2017: 27 · 2016: 16 · 2015: 9
FWCI: 2.80
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: doi.wiley.com/10.1002/tdm_license_1.1 (tdm, 162 d)
Locations: Hepatology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (DK025636)
Topics: Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Health Sciences › Medicine › Hepatology › Liver Diseases and Immunity
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
Keywords: cholestasis, primary biliary cirrhosis, primary sclerosing cholangitis, ursodeoxycholic acid, PPARα, fenofibrate, fibrates, nuclear receptors, bile acid transporters, hepatic transporters, bile acid homeostasis, CYP7A1, liver fibrosis
MeSH terms: Cholestasis, Female, Follow-Up Studies, Humans, Liver Cirrhosis, Biliary, Male, Severity of Illness Index, Ursodeoxycholic Acid, Biomarkers, Treatment Outcome, Risk Assessment, PPAR alpha, Fibric Acids

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