Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Observational Study
. 2020 Dec;108(6):1213-1223.
doi: 10.1002/cpt.1930. Epub 2020 Jul 17.

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

Nisanne S Ghonem  1 , Adam M Auclair  1 , Christopher L Hemme  2 , Gina M Gallucci  1 , Randolph de la Rosa Rodriguez  3 , James L Boyer  3 , David N Assis  3
Affiliations
Observational Study

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

Nisanne S Ghonem et al. Clin Pharmacol Ther. 2020 Dec.

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.

PubMed Disclaimer

Conflict of interest statement

CONFLICT OF INTEREST

All authors declared no competing interests for this work.

Figures

Figure 1:
Figure 1:. Combination treatment with fenofibrate reduces serum liver markers of cholestatic liver injury in patients with PBC and PSC.
Serum concentrations of: (A) ALP, (B) ALT, (C) AST, (D) total bilirubin; (E) creatinine. Data represent mean ± SEM (n=8–14), *p<0.05, **p<0.01, ***p<0.001 vs. Ursodiol monotherapy.
Figure 2:
Figure 2:. Combination treatment with fenofibrate reduces elevated serum bile acids in patients with PBC and PSC.
Scatter plots show individual patient levels: (A) total: sum of all bile acids measured; (B) primary: CA and CDCA and their respective conjugated species; (C) secondary: DCA and LCA and respective conjugated species; (D) unconjugated: sum of all unconjugated bile acids including hydroxylated bile acids and UDCA; (E) conjugated: consist of all glyco- and tauro-conjugated bile acids and LCA-S; (F) C4; (G) concentrations of serum bile acid species; (H) contribution of individual metabolites to total bile acid pool. Data are log transformed, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. control subjects.
Figure 3:
Figure 3:. Combination treatment with fenofibrate alters glycine-conjugated bile acid concentrations in patients with PBC and PSC.
Glyco-conjugates are the sum of all glycol-conjugates of CA, CDCA, DCA, and LCA. Scatter plots show individual patient serum bile acid levels, grouped together as: (A) total glycine-conjugated, (B) GCA, (C) GCDCA, and (D) GDCA. Data are log transformed, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. controls.
Figure 4:
Figure 4:. Combination treatment with fenofibrate alters taurine-conjugated bile acid concentrations in patients with PBC and PSC.
Tauro-conjugates are the sum of all tauro-conjugates of CA, CDCA, DCA, LCA, and UDCA. Scatter plots show individual patient serum bile acid levels grouped together as: (A) total taurine-conjugated, (B) TCA, (C) TCDCA, and (D) TDCA. Data are log transformed, *p<0.05, **p<0.01, ***p<0.001 vs. controls.
Figure 5:
Figure 5:. Combination treatment with fenofibrate shifts the percentage and concentrations of glycine- and taurine-conjugated bile acid in patients with PBC and PSC, closer to values observed in control subjects.
Comparisons of the ratios of glycine- and taurine-conjugated bile acid between (A) control subjects, (B) Ursodiol monotherapy in PBC, (C) combination fenofibrate in PBC, (D) Ursodiol monotherapy in PSC, and (E) combination fenofibrate in PSC.
Figure 6:
Figure 6:. Combination treatment with fenofibrate and Ursodiol shifts the bile acid composition in patients with PBC and PSC closer to those of healthy control values.
(A) PCA score plots of individual bile acids from the serum of controls, Ursodiol monotherapy and combination fenofibrate-treated patients. The first two principle components represent 66.5% of the explained variability are plotted. Data was log transformed prior to PCA analysis and was grouped by combining the Treatment and Cohort factors into a single factor of five levels (Controls, Ursodiol-PBC, Ursodiol-PSC, Combination-PBC, Combination-PSC). (B) Heatmap analysis of individual bile acids from the serum of control subjects, Ursodiol monotherapy and combination fenofibrate-treated patients. Data was log transformed prior to constructing the heatmap, which was clustered by row (metabolite). Columns represent individual samples.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Boyer JL Bile formation and secretion. Compr Physiol 3, 1035–78 (2013). - PMC - PubMed
    1. Cai SY et al. Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response. JCI Insight 2, e90780 (2017). - PMC - PubMed
    1. Leuschner M et al. Characterisation of patients with primary biliary cirrhosis responding to long term ursodeoxycholic acid treatment. Gut 46, 121–6 (2000). - PMC - PubMed
    1. 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). - PMC - PubMed
    1. Ghonem NS, Assis DN & Boyer JL Fibrates and cholestasis. Hepatology 62, 635–43 (2015). - PMC - PubMed

Publication types

MeSH terms