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

David Q.H. Wang, Frank Lammert, Beverly Paigen, Martin C. Carey

Research output: Contribution to journalArticle

96 Citations (Scopus)

Abstract

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 dis-proportionately to lecithin and bile salt outputs thereby inducing lithogeuic 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.

Original languageEnglish (US)
Pages (from-to)2066-2079
Number of pages14
JournalJournal of Lipid Research
Volume40
Issue number11
StatePublished - Jan 1 1999
Externally publishedYes

Fingerprint

Cholelithiasis
Bile Acids and Salts
Genes
Cholesterol
Lipids
Inbred AKR Mouse
Bile
Lecithins
Gallstones
Nutrition
Diet
Gallbladder
Phase separation
Cholic Acid
Liquid Crystals
Supersaturation
Cholecystectomy
Mucins
Fistula
Fasting

Keywords

  • Bile flow
  • Bile salt species
  • Dominant trait
  • Enterohepatic circulation
  • Gallstones
  • Genetics
  • Microscopy
  • Phase diagrams
  • Pool size

ASJC Scopus subject areas

  • Endocrinology

Cite this

Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice : Pathophysiology of biliary lipid secretion. / Wang, David Q.H.; Lammert, Frank; Paigen, Beverly; Carey, Martin C.

In: Journal of Lipid Research, Vol. 40, No. 11, 01.01.1999, p. 2066-2079.

Research output: Contribution to journalArticle

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abstract = "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 dis-proportionately to lecithin and bile salt outputs thereby inducing lithogeuic 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.",
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N2 - 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 dis-proportionately to lecithin and bile salt outputs thereby inducing lithogeuic 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.

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