Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice

Frank Lammert, David Q.H. Wang, Henning Wittenburg, Guylaine Bouchard, Sonja Hillebrandt, Bärbel Taenzler, Martin C. Carey, Beverly Paigen

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

We recently identified 2 Lith genes that determine cholesterol gallstone formation in C57L/J inbred mice, which show a gallstone prevalence of ∼80% on feeding 1.0% cholesterol and 0.5% cholic acid. The aim of this study was to explore if the same Lith loci contribute to the variation in gallstone susceptibility in a new experimental cross. After 12 weeks of feeding the lithogenic diet to inbred mice of strains A/J and AKR/J as well as their F1 progeny, we used microscopy of bile to assess mucin accumulation, crystallization pathways, and stone formation. Backcross progeny (n = 225) were phenotyped and genotyped selectively for microsatellite markers spanning the genome. Quantitative trait loci (QTL) affecting gallstone phenotypes were identified by linkage analysis. Both inbred strains showed accumulation of mucin gel and cholesterol supersaturation. However, only strain AKR developed gallstones (prevalence of 20%), whereas strain A showed a stable liquid crystalline state and no stones. QTL analysis identified a gallstone locus on chromosome 17 (Lith3). A second gene locus on chromosome 15 that controls mucin accumulation harbors the mucin gene Glycam1, which was shown to be expressed in gallbladder epithelia by immunohistochemistry. Gallstone and mucin loci colocalized with potential QTLs affecting the formation of cholesterol crystals. In conclusion, QTL analysis identified specific gene loci determining mucin accumulation, cholesterol crystallization, and gallstone formation. Characterization of the pathophysiologic roles of Lith3 and the new billiary mucin gene Glycam1 might provide insights into primary defects of human cholelithiasis and lead to new therapeutic strategies for prestone intervention.

Original languageEnglish (US)
Pages (from-to)1145-1154
Number of pages10
JournalHepatology
Volume36
Issue number5 II
DOIs
StatePublished - Nov 1 2002
Externally publishedYes

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Inbred AKR Mouse
Gallstones
Mucins
Crystallization
Cholesterol
Genes
Quantitative Trait Loci
Cholic Acid
Chromosomes, Human, Pair 15
Chromosomes, Human, Pair 17
Inbred Strains Mice
Cholelithiasis
Gallbladder
Bile
Microsatellite Repeats
Microscopy
Epithelium
Gels
Immunohistochemistry
Genome

ASJC Scopus subject areas

  • Hepatology

Cite this

Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice. / Lammert, Frank; Wang, David Q.H.; Wittenburg, Henning; Bouchard, Guylaine; Hillebrandt, Sonja; Taenzler, Bärbel; Carey, Martin C.; Paigen, Beverly.

In: Hepatology, Vol. 36, No. 5 II, 01.11.2002, p. 1145-1154.

Research output: Contribution to journalArticle

Lammert, F, Wang, DQH, Wittenburg, H, Bouchard, G, Hillebrandt, S, Taenzler, B, Carey, MC & Paigen, B 2002, 'Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice', Hepatology, vol. 36, no. 5 II, pp. 1145-1154. https://doi.org/10.1053/jhep.2002.36821
Lammert, Frank ; Wang, David Q.H. ; Wittenburg, Henning ; Bouchard, Guylaine ; Hillebrandt, Sonja ; Taenzler, Bärbel ; Carey, Martin C. ; Paigen, Beverly. / Lith genes control mucin accumulation, cholesterol crystallization, and gallstone formation in A/J and AKR/J inbred mice. In: Hepatology. 2002 ; Vol. 36, No. 5 II. pp. 1145-1154.
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AU - Bouchard, Guylaine

AU - Hillebrandt, Sonja

AU - Taenzler, Bärbel

AU - Carey, Martin C.

AU - Paigen, Beverly

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