The influences of cholecystectomy on the circadian rhythms of bile acids as well as the enterohepatic transporters and enzymes systems in mice

Abstract

Bile acids (BAs), the most important endogenous and signaling molecules regulate the target transporters and enzymes at transcriptional level, participate in a wide variety of processes throughout the entire gastrointestinal tract to orchestrate homeostasis in vivo. BAs and their metabolism and transportation appear to follow the clear circadian rhythms, and they are recently proposed also as the potential chronobiological signals that can affect the molecular clock mechanism. Cholecystectomy are believed to affect the circadian rhythms of BAs and the relevant enterohepatic transporters and enzymes systems and their regulatory signaling pathways, for the reason that the circadian cycle of gallbladder filling and emptying play a pivotal role in controlling the flow of bile into the intestine and the enterohepatic circulation of BAs. Here, in the present study, the circadian rhythms about BAs concentration and composition and the mRNA expression of genes involved in BAs transportation, metabolism and regulation in liver and ileum of mice with or without gallbladder were evaluated. As a result, it has been found that, mice with gallbladder exhibited significant and distinct circadian oscillations in BAs concentration, mRNA expression of enterohepatic transporters and enzymes systems and farnesoid X receptor-mediated regulatory pathways both in liver and ileum during gallbladder emptying period (1:00 AM and 1:00 PM), despite food was restricted during these periods; the circadian rhythmicity of BAs pool and hepatic and ileal BAs diminished but the BAs composition had no significant alteration in liver and ileum after cholecystectomy as compared with sham-operated mice; in parallel to the alteration of BAs levels in liver and ileum after cholecystectomy, the day/night circadian oscillations in the mRNA expression of the relevant transporting and metabolic genes and the farnesoid X receptor signaling pathway-mediated “intestine-liver†regulatory axis also shifted. In conclusion, the BAs concentration and the corresponding genes exhibit significant circadian rhythms in mice with gallbladder, and the circadian oscillations of most of the investigation factors are flattened and altered following by cholecystectomy, which could mainly ascribe to the disappearance of the filling and emptying cycle of gallbladder and might result in pathological states or drug chronopharmacology alternation. We expect that this study would provide a cue for patients with cholecystectomy.

Abbreviations: Asbt: apical sodium-dependent bile acids transporter; AUC24h: area under the 24-hour BA concentration time curve; BAs: bile acids; Bsep: bile salt export pump; β-MCA: β-muricholic acid; CA: cholic acid; CDCA: chenodeoxycholic acid; Cyp3a11: cytochrome P450 3a11 (human CYP3A4); Cyp7a1: cholesterol 7α-hydroxylase cytochrome P450 7a1; DCA: deoxycholic acid; Fxr: farnesoid X receptor; Fgf15: fibroblast growth factor 15; G-: glycine conjugated bile acid; HDCA: hyodesoxycholic acid; LCA: lithocholic acid; Mrp2: multidrug resistance-associated protein 2; NDCA: demethylation deoxycholic acid; Ntcp: Na+-taurocholate co-transporting polypeptide; Oatp2: organic anion transporting polypeptide 2; Ostα/β: heterodimeric organic solute transporters alpha and beta; Shp: small heterodimer partner; T-: taurine conjugated bile acid; UDCA: ursodeoxycholic acid.

Keywords: Bile acids; Cholecystectomy; Circadian rhythms; Enzyme; Transporter.