Abstract
The relationship between obesity and cholesterol cholelithiasis is not well understood at physiologic or genetic levels. To clarify whether obesity per se leads to increased prevalence of cholelithiasis, we examined cholesterol gallstone susceptibility in three polygenic (KK/H1J, NON/LtJ, NOD/LtJ) and five monogenic [carboxypeptidase E (Cpe fat), agouti yellow (Ay), tubby (tub), leptin (Lepob), leptin receptor (Leprdb)] murine models of obesity during in-gestion of a lithogenic diet containing dairy fat, cholesterol, and cholic acid. At 8 weeks on the diet, one strain of polygenic obese mice was resistant whereas the others revealed low or intermediate prevalence rates of cholelithiasis. Monogenic obese mice showed distinct patterns with either high or low gallstone prevalence rates depending upon the mutation. Dysfunction of the leptin axis, as evidenced by the Lepob and the Leprdb mutations, markedly reduced gallstone formation in a genetically susceptible background strain, indicating that in mice with this genetic background, physiologic leptin homeostasis is a requisite for cholesterol cholelithogenesis. In contrast, the Cpefat mutation enhanced the prevalence of cholelithiasis markedly when compared with the background strain. Since CPE converts many prohormones to hormones, a deficiency of biologically active cholecystokinin is a likely contributor to enhanced susceptibility to cholelithiasis through compromising gallbladder contractility and small intestinal motility.Because some murine models of obesity increased, whereas others decreased cholesterol gallstone susceptibility, we establish that cholesterol cholelithiasis in mice is not simply a secondary consequence of obesity per se. Rather, specific genes and distinct pathophysiological pathways are responsible for the shared susceptibility to both of these common diseases.
Highlights
The relationship between obesity and cholesterol cholelithiasis is not well understood at physiologic or genetic levels
If all obese mice developed heightened cholesterol gallstones (ChGS) frequency compared with the background strains, we could conclude that gallstones were a secondary consequence of obesity per se
If certain obesity mutations decreased ChGS prevalence rates compared with the background strains, we could think it likely that mutations in some homeostatic circuits counteract metabolic pathways leading to ChGS
Summary
Colonies of male and female mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and were acclimatized for at least 2 weeks. The Ay and Lepob mutants were obtained as congenics on a C57BL/6J (B6) background; that is, the original mutation was introgressed into the new background strain (B6) by multiple backcrossings. A The official names of the strains (and their abbreviations) are B6.Cg-Ay (Ay) , C57BL/6J-tub/ϩ (tub), B6.VLepob (Lepob), B6.Cg-m ϩ/ϩ Leprdb and BKS.Cg-m ϩ/ϩ Lepr db (Leprdb), and BKS.HRS-Cpefat/J (Cpefat), respectively It is clear from the two right-hand columns that some strains are maintained on an isogenic background (in the strain where the original mutation occurred); most mutations have been introgressed into the present backgrounds (congenics) by multiple backcrossings. After brief centrifugation of gallbladder bile (3,500 rpm for 5 min) to sediment cholesterol monohydrate crystals, total bile salt concentrations were determined using the 3␣-hydroxysteroid dehydrogenase assay [17]. Total and HDL-cholesterol (HDL-C) levels were assayed in fresh mouse blood after preparing plasma. We set significance levels at a P ഛ 0.05
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