Obeticholic acid accelerates portal vein embolization-induced liver hypertrophy in rabbits by improving bile salt homeostasis
Purpose: Obeticholic acid (OCA), an agonist of the bile salt-activated transcription factor farnesoid X receptor (FXR), accelerates liver growth following portal vein embolization (PVE) in rabbits, with largest effect seen on day 3 after PVE (volume gain of 56% vs. 26% in the control group). The aim of this research was to study underlying mechanisms.  Methods: Specimens from rabbits treated by oral gavage with OCA or vehicle (n=6-11/group) and subjected to PVE were analyzed, focusing on aspects of bile salt homeostasis, FXR-regulated gene expression in the ileum and liver, and their correlation with liver growth parameters.  Results: Following PVE, OCA treatment led to earlier normalization of serum total bile salts and reduced bile salt content in the non-embolized liver lobe. Serum levels of the hepatotoxic bile salt lithocholic acid were lower in OCA-treated rabbits on day 1 (p=0.002) and day 3 (p=0.03) post-PVE. Furthermore, serum lithocholic acid showed a strong negative correlation with liver volume gain (?=-0.726, p<0.001) and with the number of proliferating hepatocytes (?=-0.718, p=0.009). OCA treatment induced expression of mitotic entry regulator CDC25B in the non-embolized lobe. Untargeted transcript analysis identified candidate signaling factors (C1Qa, BMP3, IHH) as potential mediators of the growth-enhancing effect of OCA in this model.  Conclusion: OCA improved bile salt homeostasis, which was associated with augmented hypertrophy of the non-embolized liver lobe in rabbits subject to PVE. OCA treatment may represent an approach to increase the efficacy of PVE in patients with a small future liver remnant planned for extended partial liver resection. Overall design: Parallel-group, controlled animal intervention study: Rabbits pre-treated with OCA or vehicle (control) and subjected to PVE.