Protective Effects of 6-Ethyl Chenodeoxycholic Acid, a Farnesoid X Receptor Ligand, in Estrogen-Induced Cholestasis

TLDR

The farnesoid X receptor (FXR) regulates genes involved in bile acid synthesis, conjugation, and transport, and its dysfunction contributes to cholestatic liver diseases characterized by bile acid accumulation. The study examined the effects of 6‑ethyl chenodeoxycholic acid (6‑ECDCA), a potent FXR ligand, in a rat model of cholestasis induced by 5‑day administration of 17α‑ethynylestradiol. The authors used this estrogen‑induced cholestasis model to assess 6‑ECDCA’s impact on FXR‑mediated gene expression and bile acid transport. 6‑ECDCA activated FXR target genes (Shp, BSEP) and suppressed CYP7A1, CYP8B1, and NTCP, restored bile flow, altered bile acid composition, and protected rats from estrogen‑induced cholestasis, mirroring the effects of the synthetic FXR agonist GW4064.

Abstract

The farnesoid X receptor (FXR), an endogenous sensor for bile acids, regulates a program of genes involved in bile acid biosynthesis, conjugation, and transport. Cholestatic liver diseases are a group of immunologically and genetically mediated disorders in which accumulation of endogenous bile acids plays a role in the disease progression and symptoms. Here, we describe the effect of 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic bile acid derivative and potent FXR ligand, in a model of cholestasis induced by 5-day administration of 17α-ethynylestradiol (E₂17α) to rats. The exposure of rat hepatocytes to 1 μM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7α-hydroxylase (cyp7a1), oxysterol 12β-hydroxylase (cyp8b1), and Na⁺/taurocholate cotransporting peptide (ntcp). In vivo administration of 6-ECDCA protects against cholestasis induced by E₂17α. Thus, 6-ECDCA reverted bile flow impairment induced by E₂17α, reduced secretion of cholic acid and deoxycholic acid, but increased muricholic acid and chenodeoxycholic acid secretion. In vivo administration of 6-ECDCA increased liver expression of Shp, bsep, multidrug resistance-associated protein-2, and multidrug resistance protein-2, whereas it reduced cyp7a1 and cyp8b1 and ntcp mRNA. These changes were reproduced by GW4064, a synthetic FXR ligand. In conclusion, by demonstrating that 6-ECDCA protects against E₂17α cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestatic disorders.