HFD Exacerbates Hepatic Lipid Metabolism Disorders After Cholecystectomy by Regulating the Bile Acid and Neutrophil Recruitment

ABSTRACT Background and Aims Previous studies have suggested that cholecystectomy may lead to an elevated risk of metabolic dysfunction‐associated fatty liver disease (MAFLD). However, there is a dearth of knowledge concerning the precise effects and underlying mechanisms through which cholecystectomy influences hepatic lipid metabolism, necessitating further investigation. Methods Post‐cholecystectomy (PC) model mice were established under both normal and high‐fat diet conditions. Liver lipid metabolism, inflammation, bile acid profiles, and immune cell alterations were evaluated. Hepatocytes mimicking a high‐fat state were exposed to distinctive bile acids to investigate the chemotactic effect on neutrophils. Co‐culture experiments of hepatocytes and neutrophils evaluated lipid accumulation in hepatocytes and the expression levels of lipid metabolism‐related genes. Results Cholecystectomy under a high‐fat diet markedly disrupted hepatic lipid metabolism and exacerbated inflammation, while cholecystectomy under a normal diet did not. The bile acid profiles in the ileum and liver of PC mice underwent notable changes, along with modifications in bile acid receptors and transporters associated with enterohepatic circulation. Notably, deoxycholic acid (DCA) and tauroursodeoxycholic acid (TDCA) were identified as distinctive bile acids. Furthermore, hepatocytes in PC mice with a high‐fat diet showed an elevated level of neutrophil infiltration. Hepatocytes showed a significant increase in releasing CXCL1 and CXCL2 when administered with DCA or TDCA, suggesting an intensified chemotactic response for neutrophils. Co‐culturing neutrophils and hepatocytes exacerbated hepatocyte lipid deposition and reduced the expression of genes associated with lipid oxidative degradation. Conclusions Cholecystectomy alongside a high‐fat diet aggravates hepatic lipid metabolism disorders and inflammation by modulating hepatic bile acid profiles and promoting neutrophil recruitment.