CHOLESTEROL HOMEOSTASIS IN THE INBRED MOUSE.

Project: Research project

Project Details

Description

Cholesterol gallstones are more common in women than men in every population that has been studied. This
difference between women and men begins during puberty and continues through the childbearing years,
focusing attention upon the effects of female sex hormones. The increased risk of cholesterol gallstones in
women vs. men is related to differences in how the liver metabolizes cholesterol in response to estrogen. We
employed quantitative trait locus (QTL) analyses of an intercross between inbred strains AKR/J and A/J to
determine the subset of gallstone susceptibility genes these strains possess. Significantly, a new QTL is
detected and named Lith5 that is mapped to mouse chromosome 10. Our molecular and genetic data support
the candidacy of the ER_z gene, encoding estrogen receptor o_, as a major gene underlying Lith5, as well as
the hepatic ERa, but not ER[3, plays a critical role in 17[3-estradiol (E2)-induced gallstones. However, the
identification of lithogenic effects of Lith5 remains a significant challenge. This renewal application is
focused on identifying the lithogenic effects of Lith5 by systematically studying its pathophysiological and
biochemical functions in some "manufactured" mouse strains such as ERo_ (-/-), ATP-binding cassette
transporters GS/G8 (ABCG5/G8) (-/-), and cholecystokinin-1 receptor (CCK-1R) (-/-) mice. The applicant
proposes to (i) investigate whether targeted disruption of the murine Lith5/Era gene decreases susceptibility
to cholesterol gallstone formation; (ii) test the hypothesis that E2-Lith5/ERo_-ABCG5/G8 pathway is
responsible for biliary cholesterol hypersecretion; (iii) determine the alterations induced by Lith5_Rc_ in
hepatic cholesterol and bile salt metabolism that account for cholesterol supersaturated bile; and (iv) explore
whether E2-Lith5/ERa-CCK-1R pathway induces gallbladder hypomotility during cholesterol gallstone
formation. This work should pave the way for identifying the major Lith genes in humans, which, in turn,
should lead to strategies for early diagnosis of the trait and rational approaches to prevention.
StatusFinished
Effective start/end date9/1/998/31/10

ASJC

  • Genetics
  • Molecular Biology

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