Impaired biliary cholesterol secretion and decreased gallstone formation in apolipoprotein E–Deficient mice fed a high-cholesterol diet

doi:10.1016/S0016-5085(00)70147-8

Gastroenterology

Volume 118, Issue 4, April 2000, Pages 772-779

https://doi.org/10.1016/S0016-5085(00)70147-8 Get rights and content

Abstract

Background & Aims: Because apolipoprotein E (apoE) is a key cholesterol transport molecule involved in the hepatic uptake of chylomicron cholesterol, it may play a critical role in controlling bile cholesterol elimination and cholesterol gallstone formation induced by dietary cholesterol. To test this hypothesis, we studied biliary lipid secretion and gallstone formation in apoE-deficient mice fed cholesterol-rich diets. Methods: Bile lipid outputs and gallstone sequence events were analyzed in apoE-deficient mice fed a high-cholesterol diet or a lithogenic diet compared with control animals. Results: A high-cholesterol diet increased biliary cholesterol secretion and gallbladder bile cholesterol concentration in wild-type mice; the increase in bile cholesterol secretion was significantly attenuated in apoE-deficient mice. ApoE knockout mice fed a high-cholesterol lithogenic diet had a markedly lower frequency of gallbladder bile cholesterol crystal and gallstone formation than wild-type mice, which was most likely a result of the decreased cholesterol saturation index found in gallbladder bile of apoE-deficient mice. Conclusions: These results show that apoE expression is an important factor for regulating both biliary secretion of diet-derived cholesterol as well as diet-induced cholesterol gallstone formation in mice.

GASTROENTEROLOGY 2000;118:772-779

Section snippets

Animals and diets

Wild-type C57BL/6J and apoE KO (on a C57BL/6J genetic background) mice were originally purchased from Jackson Laboratory (Bar Harbor, ME) and bred to generate our own mouse colonies. Mice were housed in a temperature- and humidity-controlled room with a reverse-light cycle. All mice were maintained ad libitum with water and a chow diet (<0.02% [wt/wt] cholesterol; Prolab RMH3000, PMI Feeds Inc., St. Louis, MO) before the feeding experiments with cholesterol-rich diets. Male apoE KO mice (2–3

ApoE regulates the response of both plasma lipoprotein cholesterol and hepatic cholesterol content after feeding a high-cholesterol diet or a lithogenic diet

Plasma total cholesterol in wild-type C57BL/6 and apoE KO mice in response to the experimental diets is shown in Table 1. As previously described,23, 24 plasma total cholesterol concentrations increased in apoE KO mice (266 ± 31 mg/dL) compared with wild-type mice (72 ± 7 mg/dL) during the standard chow diet feeding period. After feeding a high-cholesterol diet for 4 weeks, apoE KO mice exhibited a 40% increase in plasma cholesterol concentration compared with no change in wild-type mice. When

Discussion

This study shows that apoE expression, a major plasma cholesterol transport molecule, is relevant for controlling plasma cholesterol concentration, hepatic cholesterol storage, and biliary secretion of diet-derived cholesterol in mice. In addition, apoE expression is critical for gallstone formation induced by a lithogenic diet.

In agreement with the defective hepatic uptake of CM remnants in apoE-deficient mice,²⁵ cholesterol feeding alone or feeding a cholesterol-rich lithogenic diet in apoE

Acknowledgements

The authors thank Dr. Susan Acton for critical review of the manuscript.

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Citation Excerpt :
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^☆: Address requests for reprints to: Attilio Rigotti, M.D., Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica, Marcoleta 367, Santiago, Chile. e-mail: [email protected]; fax: (56) 2-6397780.

^☆☆: Supported by Fondo Nacional de Desarrollo Científico y Tecnológico (grants 8990006 and 1971092) and Dirección de Investigación de Postgrado Universidad Católica (grant 98/01E) (Chile).

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Liver, Pancreas, and Biliary TractImpaired biliary cholesterol secretion and decreased gallstone formation in apolipoprotein E–Deficient mice fed a high-cholesterol diet☆,☆☆

Abstract

Section snippets

Animals and diets

ApoE regulates the response of both plasma lipoprotein cholesterol and hepatic cholesterol content after feeding a high-cholesterol diet or a lithogenic diet

Discussion

Acknowledgements

Gastroenterology

Gastroenterol Clin North Am

J Lipid Res

J Lipid Res

Gastroenterology

Hepatology

Am J Clin Nutr

J Lipid Res

J Lipid Res

Cell

Biochim Biophys Acta

Gastroenterology

Gastroenterology

J Lipid Res

J Lipid Res

J Lipid Res

Hepatology

Gallstones and laparoscopic cholecystectomy

JAMA

Liver, Pancreas, and Biliary Tract
Impaired biliary cholesterol secretion and decreased gallstone formation in apolipoprotein E–Deficient mice fed a high-cholesterol diet☆,☆☆