Primary biliary cholangitis (PBC) is an autoimmune liver disease characterized by the destruction of intrahepatic bile ducts, cholestasis, portal inflammation, and progressive hepatic fibrosis, with seroreactivity for antimitochondrial antibody (AMA) [1,2]. Ursodeoxycholic acid (UDCA) has been the first-line treatment for patients with PBC for decades. This hydrophilic bile acid (BA) directly reduces the proportion of hydrophobic BAs and prevents damaging biliary epithelial cells (BECs) [3]. Furthermore, UDCA reduces interferon γ (IFNγ) production from liver-infiltrating T cells in patients with PBC via the activation of NF erythroid 2-related factor 2 [4]. Recently, the farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor α (PPARα) have received significant attention; obeticholic acid and bezafibrate, agonists for FXR and PPARα, respectively, have been used as the second-line treatments for patients with PBC who had an inadequate response to UDCA [[5], [6], [7], [8]].

Murine models that mimic human diseases are generally helpful in elucidating pathogenesis and for drug discovery. To date, PBC models have included dominant-negative transforming growth factor β receptor II (dnTGFβRII) mice [9,10], Cl−/HCO3− anion exchanger 2 (AE2)a,b-deficient mice [11], interferon-γ (IFNγ) AU-rich element deletion mice [12], and 2-octynoic acid (2OA) conjugated BSA-treated mice [13,14]. These models manifest many characteristic features of PBC, including immune-mediated bile duct damage and seroreactivity for AMA; however, advanced hepatic fibrosis has not been reported.

If the reduction in hydrophobicity by UDCA is important for the amelioration of PBC, then rodents are not suitable animals to study PBC because they already have a hydrophilic BA composition similar to that of humans treated with UDCA. As primary BAs, the human liver synthesizes hydrophilic cholic acid (CA) and hydrophobic chenodeoxycholic acid (CDCA) from cholesterol. However, the mouse liver contains additional CDCA 6β-hydroxylase (CYP2C70), which converts most CDCA into extra-hydrophilic (more hydrophilic than UDCA) muricholic acids (MCAs) [15]. In addition, CA and CDCA are 7α-dehydroxylated by intestinal bacteria and transformed into more hydrophobic secondary BAs deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. However, the mouse liver converts the reabsorbed DCA and LCA back into CA and CDCA via BA 7α-rehydroxylase (CYP2A12) [15]. Thus, biliary BA composition in mice consists mainly of CA and MCAs, which are markedly hydrophilic compared to those of humans.

An innovative mouse model with a human-like hydrophobic BA composition, Cyp2a12/Cyp2c70 double knockout (DKO) mice, has recently been reported [15]. In this study, we investigated the effects of hydrophobic bile acids on the pathogenesis of PBC in DKO mice treated with 2OA.