Obeticholic acid accelerates portal vein embolization-induced liver hypertrophy in rabbits by improving bile salt homeostasis

Obeticholic acid (OCA), a potent agonist of the bile salt-activated nuclear receptor farnesoid X receptor (FXR), accelerates liver hypertrophy after portal vein embolization (PVE), but the mechanisms underlying this effect are incompletely understood. In a rabbit model of PVE, New Zealand White rabbits received OCA (10 mg/kg/day) or vehicle by oral gavage before and after embolization. We quantified systemic and hepatic bile salt pools, profiled FXR-regulated genes in ileum and liver, and related these parameters to volumetric and histological indices of regeneration. OCA shifted bile salt composition towards a more hydrophobic profile and improved homeostasis, with earlier normalization of serum total bile salts, reduced bile salt content in the non-embolized (hypertrophic) lobe, and lower circulating levels of the hepatotoxic bile salt lithocholic acid. Serum lithocholic acid strongly and inversely correlated with both caudal liver volume gain and hepatocyte proliferation. In the hypertrophic lobe, OCA markedly suppressed expression of CYP7A1, reduced circulating levels of the bile salt synthesis marker 7-alpha-hydroxy-4-cholesten-3-one, and increased expression of the basolateral bile salt exporter SLC51A/B, consistent with reduced bile salt synthesis and enhanced sinusoidal efflux. OCA also induced the mitotic entry regulator CDC25B. RNA sequencing identified ileal and hepatic signaling candidates, including C1q subunits, bone morphogenetic protein 3 (BMP3), and Indian hedgehog (IHH), which correlated with liver growth. These data indicate that FXR agonism by OCA promotes PVE-induced liver regeneration by improving bile salt homeostasis and modulating gut–liver growth signaling, supporting further evaluation of FXR agonists to enhance future liver remnant hypertrophy before major hepatectomy. • Large animal PVE model shows OCA accelerates future liver remnant hypertrophy. • OCA reshapes bile salt homeostasis and lowers hepatotoxic lithocholic acid levels. • Serum lithocholic acid inversely correlates with liver volume gain and proliferation. • OCA represses CYP7A1, induces SLC51A/B and CDC25B, and unloads bile salts from liver. • RNAseq reveals FXR-dependent gut-liver signals (C1q, BMP3, IHH) linked to growth.