Short-term obeticholic acid treatment does not impact cholangiopathy in Cyp2c70-deficient mice with a human-like bile acid composition

Rumei Li, Milaine V Hovingh, Martijn Koehorst, Pim de Blaauw, Henkjan J Verkade, Jan Freark de Boer*, Folkert Kuipers*

*Corresponding author for this work

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Abstract

Cyp2c70-/- mice with a human-like bile acid (BA) composition, lacking hydrophilic muricholic acids (MCAs), have been reported to display cholangiopathy and biliary fibrosis with female preponderance that can be reversed by ursodeoxycholic acid (UDCA). Obeticholic acid (OCA), a steroidal BA-like FXR agonist, has been shown to improve liver function in patients with primary biliary cholangitis and is approved as second-line treatment for patients with an inadequate response or intolerance to UDCA. Here, we investigated the impact of OCA on BA hydrophobicity and cholangiopathy in Cyp2c70-/- mice. Male and female wild-type (WT) and Cyp2c70-/- mice were fed a chow diet with or without 10 mg/kg/day OCA for 4 weeks. OCA accounted for 1-5% of biliary BAs, with larger enrichments in Cyp2c70-/- than in WT mice. In WT mice, OCA induced a more hydrophilic, MCA-rich BA pool. In Cyp2c70-/- mice, however, BA pool became more hydrophobic with a larger proportion of chenodeoxycholic acid, attributable to a reduction of BA 12α-hydroxylation. OCA treatment reduced fecal BA excretion, indicating repression of hepatic BA synthesis in both WT and Cyp2c70-/- mice. OCA did, however, not impact on markers of liver (dys)function in plasma nor did it ameliorate cholangiopathy and fibrosis in male or female Cyp2c70-/- mice. OCA treatment also did not affect the expression of genes involved in fibrosis, inflammation and cellular senescence. In conclusion, 4 weeks of OCA treatment oppositely modulates the hydrophobicity of the BA pool in WT and Cyp2c70-/- mice, but does not improve or worsen the characteristic sex-dependent liver pathology in Cyp2c70-/- mice.

Original languageEnglish
Article number159163
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1867
Issue number8
DOIs
Publication statusPublished - Aug-2022

Keywords

  • FXR agonist
  • Liver
  • Hydrophobicity
  • Cyp8b1
  • Inflammation
  • Humanized mouse model
  • PRIMARY BILIARY-CIRRHOSIS
  • X RECEPTOR ACTIVATION
  • CHOLESTEROL
  • FXR
  • MULTICENTER
  • CELLS

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