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Cholecystectomy inhibits fasting hepatic fatty acid oxidation in mice

ABSTRACT:

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.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse-phase, Liquid Chromatography MS - positive - reverse-phase

PROVIDER: MTBLS13476 | MetaboLights | 2026-01-13

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13476_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13476_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13476_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13476_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Gallstone disease is a major contributor to health care costs in the United States. Approximately 12 % of the U.S. population has gallstones. As a result, more than 700,000 cholecystectomies are performed in this country each year. Many of these patients are obese and have a positive family history; but surprisingly, little is known about the link between obesity, genetics and gallstone formation. Obese individuals have been shown to have supersaturated bile, larger gallbladder fasting volumes and impaired gallbladder emptying. We have recently demonstrated that leptin plays a role in gallbladder motility. In an effort to understand the genetic basis for these observations, we tested the hypothesis that leptin would alter gallbladder gene expression. Methods: Affymetrix oligonucleotide microarrays 430 2.0 were used to compare gallbladder gene expression profiles from 12 week old control saline-treated leptin-deficient (Lep ob) and from leptin-treated Lep ob female mice. Analyses were performed on pooled RNA (n=4) from the gallbladders of 12 saline-treated Lep ob mice and from 12 Lep ob mice which were administered daily IP 5 ug/g of recombinant murine leptin for 4 weeks. Resulting data were analyzed utilizing Gene Chip Operating Software or MAS 5.0. Results: Of the genes analyzed 314 were upregulated and 108 were downregulated by leptin administration. Numerous genes related to gallstone pathogenesis, gallbladder absorption/secretion, inflammatory cytokines, and insulin resistance were altered by leptin. Experiment Overall Design: Female B6.V-lepob obese mice (n=24) aged 7 weeks were obtained from The Jackson Laboratory (Bar Harbor, ME). Upon arrival, mice were placed on a standard chow diet and were allowed to acclimate for 1 week before starting the experiment. For leptin treatments, mice received daily intraperitoneal injections of either recombinant mouse leptin (R&D Systems, Minneapolis, MN) (n=12) at a dose of 5 µg/g body weight or with saline as a control (n=12) for 4 weeks. At 12 weeks of age, mice were fasted overnight with free access to water. The following morning the mice underwent cholecystectomy. Three gallbladders were pooled to create 4 pools in each treatment and total RNA was isolated. Affymetrix murine 430 2.0 arrays were utilized to examine altered gallbladder gene expression as a result of leptin administration. The resulting data was analyzed utlizing Gene Chip Operating Software or MAS 5.0.

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Cholecystectomy inhibits fasting hepatic fatty acid oxidation in mice

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