Cholecystectomy and risk of metabolic syndrome

Abstract

The gallbladder physiologically concentrates and stores bile during fasting and provides rhythmic bile secretion both during fasting and in the postprandial phase to solubilize dietary lipids and fat-soluble vitamins. Bile acids (BAs), major lipid components of bile, play a key role as signaling molecules in modulating gene expression related to cholesterol, BA, glucose and energy metabolism. Cholecystectomy is the most commonly performed surgical procedure worldwide in patients who develop symptoms and/or complications of cholelithiasis of any type. Cholecystectomy per se, however, might cause abnormal metabolic consequences, i.e., alterations in glucose, insulin (and insulin-resistance), lipid and lipoprotein levels, liver steatosis and the metabolic syndrome. Mechanisms are likely mediated by the abnormal transintestinal flow of BAs, producing metabolic signaling that acts without gallbladder rhythmic function and involves the BAs/farnesoid X receptor (FXR) and the BA/G protein-coupled BA receptor 1 (GPBAR-1) axes in the liver, intestine, brown adipose tissue and muscle. Alterations of intestinal microbiota leading to distorted homeostatic processes are also possible. According to this view, cholecystectomy, via BA-induced changes in the enterohepatic circulation, is a risk factor for the metabolic abnormalities and becomes another “fellow traveler” with, or another risk factor for the metabolic syndrome.

Keywords: Bile acids; Cholecystectomy; Cholesterol; Enterohepatic circulation; Gallbladder; Gallstone disease; Nuclear receptors.

Conflict of interest statement

Disclosure/conflict of interest

The authors declare no conflict of interest.

Figures

Fig. 1A.

Potential mechanisms pointing to the links between cholecystectomy and metabolic disturbances. 1) Subjects living in industrialized countries tend to accumulate metabolic abnormalities, eventually leading to the metabolic syndrome and additional “fellow travellers” such as cholesterol cholelithiasis and liver steatosis (nonalcoholic fatty liver disease, NAFLD). 2) A subgroup of subjects (not necessarily metabolically unhealthy), may develop pigment gallstones. 3) At this stage, gallstone patients usually require cholecystectomy if asymptomatic cholelithiasisbecomes symptomatic, with or without complications. 4) The loss of multiple gallbladder functions leads to accelerated enterohepatic circulation of both hepatic primary (cholic acid, chenodeoxycholic acid), and intestinal secondary (deoxycholic acid, litocholic acid) and tertiary (ursodeoxycholic acid) bile acids (BAs).Under these circumstances, changes may occurr at the level of interaction between: a) intestinal BAs - farnesoid X receptor (FXR) and release of fibroblast growth factor 19 (FGF19); b) intestinal BAs - G-protein-coupled bile acid receptor-1 (GPBAR-1, also known as TGR5) and release of glucagon-like peptide-1 and 2 (GLP1/2) and peptide YY (PYY) with important metabolic effects on glucose, insulin metabolism and appetite; c) serum BAs and hepatocyte FXR and Kupffer cell GPBAR-1 with inhibition of BA synthesis as well as on brown adipose tissue and striated muscle GPBAR-1 with additional metabolic effects. See text for details. 5) A role for single nucleotide polymorphisms (SNP) is also emerging with influence on the nuclear receptor-mediated mechanisms leading to the development of metabolic syndrome and the level of risk in some individuals. LXR, liver X receptor; PXR, pregnane X receptor.

Fig. 1B.

Additional pathways linking cholecystectomy and metabolic disturbances, including liver steatosis. After cholecystectomy, the dynamic reservoir function of the gallbladder controlled by neural mechanisms and entero-hormones (i.e. stimulatory fasting motilin and postprandial cholecystokinin and inhibitory myorelaxant vasoactive intestinal peptide, VIP) is lost. Also lost are the gallbladderreceptors fibroblast growth factor receptor 4 (FGFR4), targeted by FGF19 and G protein-coupled receptor (GPBAR-1) targeted by BAs both leading to gallbladder relaxation. Improved clinical conditions, increased caloric and fat intake might account for some of the metabolic changes associated with production of adypocyte-derived products and a chronic pro-inflammatory status. While the BA pool decreases and the intestine acts as the major bile acid reservoir, cholecystectomy increases the enterohepatic recirculation rates of BAs at least twice as often as normal especially during fasting, a step leading to accelerated intestinal recycling, increased secretion rates of BAs and cholesterol in bile with preserved fat absorption. Increased bacterial deconjugation and dehydroxylation of BAs will increase the proportion of secondary BAs due to accelerated intestinal recycling and likely changes of intestinal microbiota. Cholecystectomy is also associated to a twofold increase in BA acid synthesis, irrespective of a significant reduction in serum FGF19 concentrations which is mostly gallbladder-derived. Further metabolic effects of cholecystectomy are mediated by elevated serum BA concentrations, increased tissue exposure to BAs and increased basal metabolic rate. GPBAR-1 stimulation might decrease after cholecystectomy, but GPBAR-1-mediated metabolic effects include slight deterioration of postprandial glycemic, increased serum and hepatic triglyceride levels, and production of very low density lipoproteins. The changes occurr irrespective of gallstone disease per se and point to the steatogenic effect in the liver and propension to metabolic syndrome. Epigenetic changes might also play a role in the pro-steatogenic effect in the liver. Abbreviations: ChREBP, carbohydrate-responsive element-binding protein; DNL, de novo lipogenesis; IL, interleukin; PKCε protein kinase Cε; SREBP, sterol regulatory element-binding protein 1; TNF, tumor necrosis factor. Symbols: ↑ , increased; ↓, decreased; (−), inhibition.