HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, D. Q-H. Articles by Carey, M. C. Search for Related Content PubMed PubMed Citation Articles by Wang, D. Q-H. Articles by Carey, M. C. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 40, 2066-2079, November 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: pathophysiology of biliary lipid secretion

Correspondence to: Martin C. Carey

The inbred C57L strain but not the AKR strain of mice carry Lith genes that determine cholesterol gallstone susceptibility. When C57L mice are fed a lithogenic diet containing 15% fat, 1% cholesterol, and 0.5% cholic acid, gallbladder bile displays rapid cholesterol supersaturation, mucin gel accumulation, increases in hydrophobic bile salts, and rapid phase separation of solid and liquid crystals, all of which contribute to the high cholesterol gallstone prevalence rates (D. Q-H. Wang, B. Paigen, and M. C. Carey. J. Lipid Res. 1997. 38: 1395;–1411). We have now determined the hepatic secretion rates of biliary lipids in fasting male and female C57L and AKR mice and the intercross (C57L x AKR)F₁ before and at frequent intervals during feeding the lithogenic diet for 56 days. Bile flow and biliary lipid secretion rates were measured in the first hour of an acute bile fistula and circulating bile salt pool sizes were determined by the "washout" technique after cholecystectomy. Compared with AKR mice, we found that i) C57L and F₁ mice on chow displayed significantly higher secretion rates of all biliary lipids, and larger bile salt pool sizes, as well as higher bile salt-dependent and bile salt-independent flow rates; ii) the lithogenic diet further increased biliary cholesterol and lecithin outputs, but bile salt outputs remained constant. Biliary coupling of cholesterol to lecithin increased approximately 30%, setting the biophysical conditions necessary for cholesterol phase separation in the gallbladder; and iii) no gender differences in lipid secretion rates were noted but male mice exhibited significantly more hydrophobic bile salt pools than females.

We conclude that in gallstone-susceptible mice, Lith genes determine increased outputs of all biliary lipids but promote cholesterol hypersecretion disproportionately to lecithin and bile salt outputs thereby inducing lithogenic bile formation.—Wang, D. Q-H., F. Lammert, B. Paigen, and M. C. Carey. Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: pathophysiology of biliary lipid secretion. J. Lipid Res. 1999. 40: 2066;–2079.

Supplementary key words: gallstones, enterohepatic circulation, genetics, phase diagrams, pool size, bile salt species, bile flow, dominant trait, microscopy

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R. Liu, J. Iqbal, C. Yeang, D. Q.-H. Wang, M. M. Hussain, and X.-C. Jiang Phospholipid Transfer Protein-Deficient Mice Absorb Less Cholesterol Arterioscler. Thromb. Vasc. Biol., September 1, 2007; 27(9): 2014 - 2021. [Abstract] [Full Text] [PDF]

				J. Wang, C. Einarsson, C. Murphy, P. Parini, I. Bjorkhem, M. Gafvels, and G. Eggertsen Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice J. Lipid Res., February 1, 2006; 47(2): 421 - 430. [Abstract] [Full Text] [PDF]

				K. J. van Erpecum, D. Q-H. Wang, A. Moschetta, D. Ferri, M. Svelto, P. Portincasa, J.-J. Hendrickx, M. Schipper, and G. Calamita Gallbladder histopathology during murine gallstone formation: relation to motility and concentrating function J. Lipid Res., January 1, 2006; 47(1): 32 - 41. [Abstract] [Full Text] [PDF]

				T. Jiang, Z. Wang, G. Proctor, S. Moskowitz, S. E. Liebman, T. Rogers, M. S. Lucia, J. Li, and M. Levi Diet-induced Obesity in C57BL/6J Mice Causes Increased Renal Lipid Accumulation and Glomerulosclerosis via a Sterol Regulatory Element-binding Protein-1c-dependent Pathway J. Biol. Chem., September 16, 2005; 280(37): 32317 - 32325. [Abstract] [Full Text] [PDF]

				M. K. Wu and D. E. Cohen Altered hepatic cholesterol metabolism compensates for disruption of phosphatidylcholine transfer protein in mice Am J Physiol Gastrointest Liver Physiol, September 1, 2005; 289(3): G456 - G461. [Abstract] [Full Text] [PDF]

				S. S. Sundaram, P. F. Whitington, and R. M. Green Steatohepatitis develops rapidly in transgenic mice overexpressing Abcb11 and fed a methionine-choline-deficient diet Am J Physiol Gastrointest Liver Physiol, June 1, 2005; 288(6): G1321 - G1327. [Abstract] [Full Text] [PDF]

				M. K. Wu, H. Hyogo, S. K. Yadav, P. M. Novikoff, and D. E. Cohen Impaired response of biliary lipid secretion to a lithogenic diet in phosphatidylcholine transfer protein-deficient mice J. Lipid Res., March 1, 2005; 46(3): 422 - 431. [Abstract] [Full Text] [PDF]

				L.-P. Duan, H. H. Wang, and D. Q-H. Wang Cholesterol absorption is mainly regulated by the jejunal and ileal ATP-binding cassette sterol efflux transporters Abcg5 and Abcg8 in mice J. Lipid Res., July 1, 2004; 45(7): 1312 - 1323. [Abstract] [Full Text] [PDF]

				A. del Castillo-Olivares, J. A. Campos, W. M. Pandak, and G. Gil The Role of {alpha}1-Fetoprotein Transcription Factor/LRH-1 in Bile Acid Biosynthesis: A KNOWN NUCLEAR RECEPTOR ACTIVATOR THAT CAN ACT AS A SUPPRESSOR OF BILE ACID BIOSYNTHESIS J. Biol. Chem., April 16, 2004; 279(16): 16813 - 16821. [Abstract] [Full Text] [PDF]

				H. H. Wang, N. H. Afdhal, S. J. Gendler, and D. Q-H. Wang Targeted disruption of the murine mucin gene 1 decreases susceptibility to cholesterol gallstone formation J. Lipid Res., March 1, 2004; 45(3): 438 - 447. [Abstract] [Full Text] [PDF]

				V. A. B. Drover and L. B. Agellon Regulation of the Human Cholesterol 7{alpha}-Hydroxylase Gene (CYP7A1) by Thyroid Hormone in Transgenic Mice Endocrinology, February 1, 2004; 145(2): 574 - 581. [Abstract] [Full Text] [PDF]

				A. Figge, F. Lammert, B. Paigen, A. Henkel, S. Matern, R. Korstanje, B. L. Shneider, F. Chen, E. Stoltenberg, K. Spatz, et al. Hepatic Overexpression of Murine Abcb11 Increases Hepatobiliary Lipid Secretion and Reduces Hepatic Steatosis J. Biol. Chem., January 23, 2004; 279(4): 2790 - 2799. [Abstract] [Full Text] [PDF]

				G A Clarke, G Bouchard, B Paigen, and M C Carey Cholesterol synthesis inhibition distal to squalene upregulates biliary phospholipid secretion and counteracts cholelithiasis in the genetically prone C57L/J mouse Gut, January 1, 2004; 53(1): 136 - 142. [Abstract] [Full Text] [PDF]

				G.-Z. Tao, D. M. Toivola, B. Zhong, S. A. Michie, E. Z. Resurreccion, Y. Tamai, M. M. Taketo, and M. B. Omary Keratin-8 null mice have different gallbladder and liver susceptibility to lithogenic diet-induced injury J. Cell Sci., November 15, 2003; 116(22): 4629 - 4638. [Abstract] [Full Text] [PDF]

				M. A. Lyons, H. Wittenburg, R. Li, K. A. Walsh, M. R. Leonard, R. Korstanje, G. A. Churchill, M. C. Carey, and B. Paigen Lith6: a new QTL for cholesterol gallstones from an intercross of CAST/Ei and DBA/2J inbred mouse strains J. Lipid Res., September 1, 2003; 44(9): 1763 - 1771. [Abstract] [Full Text] [PDF]

				M. A. Lyons, H. Wittenburg, R. Li, K. A. Walsh, M. R. Leonard, G. A. Churchill, M. C. Carey, and B. Paigen New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice Physiol Genomics, August 15, 2003; 14(3): 225 - 239. [Abstract] [Full Text] [PDF]

				D. Q.-H. Wang, S. Tazuma, D. E. Cohen, and M. C. Carey Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: studies in the gallstone-susceptible mouse Am J Physiol Gastrointest Liver Physiol, August 8, 2003; 285(3): G494 - G502. [Abstract] [Full Text] [PDF]

				H. Hyogo, S. Roy, and D. E. Cohen Restoration of gallstone susceptibility by leptin in C57BL/6J ob/ob mice J. Lipid Res., June 1, 2003; 44(6): 1232 - 1240. [Abstract] [Full Text] [PDF]

				D. Q-H. Wang and M. C. Carey Measurement of intestinal cholesterol absorption by plasma and fecal dual-isotope ratio, mass balance, and lymph fistula methods in the mouse: an analysis of direct versus indirect methodologies J. Lipid Res., May 1, 2003; 44(5): 1042 - 1059. [Abstract] [Full Text] [PDF]

				D. Q-H. Wang Aging per se is an independent risk factor for cholesterol gallstone formation in gallstone susceptible mice J. Lipid Res., November 1, 2002; 43(11): 1950 - 1959. [Abstract] [Full Text] [PDF]

				D. Q-H. Wang and S. Tazuma Effect of {beta}-muricholic acid on the prevention and dissolution of cholesterol gallstones in C57L/J mice J. Lipid Res., November 1, 2002; 43(11): 1960 - 1968. [Abstract] [Full Text] [PDF]

				J. H. Miyake, X. T. Duong-Polk, J. M. Taylor, E. Z. Du, L. W. Castellani, A. J. Lusis, and R. A. Davis Transgenic Expression of Cholesterol-7-{alpha}-Hydroxylase Prevents Atherosclerosis in C57BL/6J Mice Arterioscler. Thromb. Vasc. Biol., January 1, 2002; 22(1): 121 - 126. [Abstract] [Full Text] [PDF]

				M. Fuchs, A. Hafer, C. Munch, F. Kannenberg, S. Teichmann, J. Scheibner, E. F. Stange, and U. Seedorf Disruption of the Sterol Carrier Protein 2 Gene in Mice Impairs Biliary Lipid and Hepatic Cholesterol Metabolism J. Biol. Chem., December 14, 2001; 276(51): 48058 - 48065. [Abstract] [Full Text] [PDF]

				D. Q-H. Wang, B. Paigen, and M. C. Carey Genetic factors at the enterocyte level account for variations in intestinal cholesterol absorption efficiency among inbred strains of mice J. Lipid Res., November 1, 2001; 42(11): 1820 - 1830. [Abstract] [Full Text] [PDF]

				B. PAIGEN, N. J. SCHORK, K. L. SVENSON, Y.-C. CHEAH, J.-L. MU, F. LAMMERT, D. Q.-H. WANG, G. BOUCHARD, and M. C. CAREY Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice Physiol Genomics, November 9, 2000; 4(1): 59 - 65. [Abstract] [Full Text] [PDF]

				F. Lammert, D. Q-H. Wang, B. Paigen, and M. C. Carey Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: integrated activities of hepatic lipid regulatory enzymes J. Lipid Res., November 1, 1999; 40(11): 2080 - 2090. [Abstract] [Full Text]

				M. C. Hunt, Y.-Z. Yang, G. Eggertsen, C. M. Carneheim, M. Gafvels, C. Einarsson, and S. E. H. Alexson The Peroxisome Proliferator-activated Receptor alpha (PPARalpha ) Regulates Bile Acid Biosynthesis J. Biol. Chem., September 8, 2000; 275(37): 28947 - 28953. [Abstract] [Full Text] [PDF]

				F. M. Gregoire, Q. Zhang, S. J. Smith, C. Tong, D. Ross, H. Lopez, and D. B. West Diet-induced obesity and hepatic gene expression alterations in C57BL/6J and ICAM-1-deficient mice Am J Physiol Endocrinol Metab, March 1, 2002; 282(3): E703 - E713. [Abstract] [Full Text] [PDF]

				H. Wittenburg, F. Lammert, D. Q.-H. Wang, G. A. Churchill, R. Li, G. Bouchard, M. C. Carey, and B. Paigen Interacting QTLs for cholesterol gallstones and gallbladder mucin in AKR and SWR strains of mice Physiol Genomics, February 11, 2002; 8(1): 67 - 77. [Abstract] [Full Text] [PDF]