Application of Quantitative Targeted Absolute Proteomics to Profile Protein Expression Changes of Hepatic Transporters and Metabolizing Enzymes During Cholic Acid-Promoted Liver Regeneration

Abstract

Preoperative administration of cholic acid (CA) may be an option to increase the liver volume before elective liver resection surgery, so it is important to understand its effects on liver functionality for drug transport and metabolism. The purpose of this study is to clarify the absolute protein expression dynamics of transporters and metabolizing enzymes in the liver of mice fed with CA-containing diet for 5 days (CA1) and mice fed with CA-containing diet for 5 days followed by diet without CA for 7 days (CA2), in comparison with non-CA-fed control mice. The CA1 group showed the increased liver weight, cell proliferation index, and oxidative stress, but no increase in apoptosis. Quantitative targeted absolute proteomics revealed (1) decreases in basolateral bile acid transporters Na+-taurocholate cotransporting polypeptide, anion transporting polypeptide (oatp) 1a1, and oatp1b2, bile acid synthesis-related enzymes cyp7a1 and cyp8b1, and drug transporters breast cancer resistance protein, multidrug resistance-associated protein 6, ent1, and oatp2b1; and (2) increases in glutathione biosynthetic enzymes and drug-metabolizing enzyme cyp3a11. Liver concentrations of reduced and oxidized glutathione were both increased. In the CA2 group, the increased liver weight was maintained, whereas the biochemical features and protein profiles were restored to the non-CA-fed control levels. These findings suggest that CA administration alters liver functionality per body during liver regeneration and restoration.