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Journal of Lipid Research, Vol. 43, 1105-1113, July 2002
Copyright © 2002 by Lipid Research, Inc.

Cholesterol gallstone formation in overweight mice establishes that obesity per se is not linked directly to cholelithiasis risk

Guylaine Bouchard^*,, Derek Johnson^*, Tonya Carver, Beverly Paigen and Martin C. Carey^1,*

^* Department of Medicine, Harvard Medical School, Division of Gastroenterology, Brigham and Women's Hospital and Harvard Digestive Diseases Center, Boston, MA
The Jackson Laboratory, Bar Harbor, ME

¹ To whom correspondence should be addressed. e-mail: mccarey{at}rics.bwh.harvard.edu

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 (A^y), tubby (tub), leptin (Lep^ob), leptin receptor (Lepr ^db)] 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 Lep^ob and the Lepr ^db 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 Cpe ^fat 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.

Abbreviations: A^y, agouti yellow; B6, C57BL/6J inbred mouse strain; BKS, C57BLKS/J inbred mouse strain; CCK, cholecystokinin; CCKAR, cholecystokinin A receptor; ChGS, cholesterol gallstones; CPE, carboxypeptidase E; CSI, cholesterol saturation index; LEP, leptin; LEPR, leptin receptor; tub, tubby

Supplementary key words cholesterol saturation index • monogenic and polygenic obesity genes • carboxypeptidase E • leptin • leptin receptor • cholecystokinin

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