Cholecystectomy inhibits fasting hepatic fatty acid oxidation in mice

Cholecystectomy is associated with an increased risk of metabolic syndrome (MetS); however, the underlying mechanism remains unknown. The gallbladder acts as a storage organ for hepatic bile and regulates the feeding/fasting cycles of bile acid (BA) flow in the enterohepatic circulation (EHC). In this study, we aimed to use C57BL/6 mice to investigate the effects of cholecystectomy in the regulation of glucose homeostasis and bile acid metabolism with metabolomics and quantitative RT-PCR. The results show that cholecystectomy increases fasting hepatic BA levels by enhancing EHC. Livers from cholecystectomized (XGB) mice displayed suppression of genes involved in fatty acid oxidation (FAO), abnormal lipid accumulation, and marked remodeling of their metabolomic profiles, particularly a reduction in FAO intermediate acylcarnitines. Many FAO genes were transcriptional targets of the peroxisome proliferator-activated receptor α (PPARα), and BA inhibited PPARα, resulting in impeded FAO. Consistent with this, blocking intestinal BA uptake using an apical sodium-BA transporter inhibitor enhanced fasting hepatic FAO levels and ameliorated metabolic disorders in XGB mice. Analysis of patient peripheral blood revealed directional trends in bile acid and fatty acid metabolites that were consistent with the metabolic disruptions observed in mice. Nevertheless, these findings suggest that cholecystectomy could inhibit fasting hepatic FAO by disturbing the EHC of BA, and reveal the role of the gallbladder in coordinating PPARα-regulated FAO in the liver.