Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis

Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator–activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenof...

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Autores principales:	Gina M. Gallucci, Jocelyn Trottier, Christopher Hemme, David N. Assis, James L. Boyer, Olivier Barbier, Nisanne S. Ghonem
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/4e62934da7614ae5b608e33161781e61
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spelling	oai:doaj.org-article:4e62934da7614ae5b608e33161781e612021-11-30T13:39:17ZAdjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis2471-254X10.1002/hep4.1787https://doaj.org/article/4e62934da7614ae5b608e33161781e612021-12-01T00:00:00Zhttps://doi.org/10.1002/hep4.1787https://doaj.org/toc/2471-254XAccumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator–activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up‐regulate BA‐glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13‐15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145‐160 mg/day) as standard of care. Serum BA and BA‐glucuronide concentrations were measured by liquid chromatography–mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (−76%, P < 0.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (−54%), and increased serum BA‐glucuronides (+2.1‐fold, P < 0.01) versus ursodiol monotherapy. The major serum BA‐glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid–6G (+3.7‐fold, P < 0.01), hyocholic acid–6G (+2.6‐fold, P < 0.05), chenodeoxycholic acid (CDCA)–3G (−36%), and lithocholic acid (LCA)–3G (−42%) versus ursodiol monotherapy. Fenofibrate also up‐regulated the expression of uridine 5′‐diphospho‐glucuronosyltransferases and multidrug resistance–associated protein 3 messenger RNA in primary human hepatocytes. Pearson’s correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA‐3G (r2 = 0.62, P < 0.0001), deoxycholic acid (DCA)‐3G (r2 = 0.48, P < 0.0001), and LCA‐3G (r2 = 0.40, P < 0.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA‐glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA‐glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα‐mediated anti‐cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA‐glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.Gina M. GallucciJocelyn TrottierChristopher HemmeDavid N. AssisJames L. BoyerOlivier BarbierNisanne S. GhonemWileyarticleDiseases of the digestive system. GastroenterologyRC799-869ENHepatology Communications, Vol 5, Iss 12, Pp 2035-2051 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Diseases of the digestive system. Gastroenterology RC799-869 Gina M. Gallucci Jocelyn Trottier Christopher Hemme David N. Assis James L. Boyer Olivier Barbier Nisanne S. Ghonem Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis
description	Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator–activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up‐regulate BA‐glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13‐15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145‐160 mg/day) as standard of care. Serum BA and BA‐glucuronide concentrations were measured by liquid chromatography–mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (−76%, P < 0.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (−54%), and increased serum BA‐glucuronides (+2.1‐fold, P < 0.01) versus ursodiol monotherapy. The major serum BA‐glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid–6G (+3.7‐fold, P < 0.01), hyocholic acid–6G (+2.6‐fold, P < 0.05), chenodeoxycholic acid (CDCA)–3G (−36%), and lithocholic acid (LCA)–3G (−42%) versus ursodiol monotherapy. Fenofibrate also up‐regulated the expression of uridine 5′‐diphospho‐glucuronosyltransferases and multidrug resistance–associated protein 3 messenger RNA in primary human hepatocytes. Pearson’s correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA‐3G (r2 = 0.62, P < 0.0001), deoxycholic acid (DCA)‐3G (r2 = 0.48, P < 0.0001), and LCA‐3G (r2 = 0.40, P < 0.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA‐glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA‐glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα‐mediated anti‐cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA‐glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.
format	article
author	Gina M. Gallucci Jocelyn Trottier Christopher Hemme David N. Assis James L. Boyer Olivier Barbier Nisanne S. Ghonem
author_facet	Gina M. Gallucci Jocelyn Trottier Christopher Hemme David N. Assis James L. Boyer Olivier Barbier Nisanne S. Ghonem
author_sort	Gina M. Gallucci
title	Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis
title_short	Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis
title_full	Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis
title_fullStr	Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis
title_full_unstemmed	Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis
title_sort	adjunct fenofibrate up‐regulates bile acid glucuronidation and improves treatment response for patients with cholestasis
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/4e62934da7614ae5b608e33161781e61
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Adjunct Fenofibrate Up‐regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis

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