Genetic analysis of cholesterol gallstone formation: Searching for Lith (gallstone) genes

Abstract

The genetics of cholesterol cholelithiasis is complex because a number of interacting genes regulate biliary cholesterol homeostasis. Quantitative trait locus (QTL) analysis is a powerful method for identifying primary rate-limiting genetic defects and discriminating them from secondary downstream lithogenic effects caused by mutations of the primary genes. The subsequent positional cloning of such genes responsible for QTLs may lead to the discovery of pathophysiologic functions of Lith (gallstone) genes. In this review, we present a map of candidate genes for Lith genes that may determine gallstone susceptibility in mice. The physical-chemical, pathophysiologic, and genetic studies of Lith genes in bile, liver, gallbladder, and intestine will be crucial for elucidating the genetic mechanisms of cholesterol gallstone disease in mice and in humans. Because exceptionally close homology exists between mouse and human genomes, the orthologous human LITH genes can often be recognized after mouse genes are identified.

Disruption of the Murine Protein Kinase Cβ Gene Promotes Gallstone Formation and Alters Biliary Lipid and Hepatic Cholesterol Metabolism

“…However, lack of a significant change in hepatic SHP content between genotypes argues against involvement of SHP-dependent pathways in CYP7A1 repression. 4 Alternately, PKC␤ directly phosphorylates nuclear receptors (LXR, FXR, and PPAR␣) and/or the transcription factor SREBP-1c and suppresses CYP7A1 transcription, which is in line with earlier reports showing the ability of PKCs to phosphorylate and modify the above transcription factors (59 -63). The absence of changes in LXR (ABCG5/8) or FXR (ABCB11) target genes argues against a mechanism involving these transcriptional regulators.…”

“…Approximately 12% of individuals in the United States are affected by gallstones with more than 750,000 cholecystectomies being performed each year (1,2). The pathogenesis of gallstone disease is multifactorial, involving interactions between genetic and environmental factors that result in bile supersaturation, gallbladder hypomotility, and precipitation/nucleation of cholesterol microcrystals (3,4). Obesity, aging, estrogen treatment, and diabetes are consistently associated with a higher risk of gallstones (5,6).…”

“…The signaling mechanisms that link changes in the triglyceride (TG) 3 content of the body and impaired glucose metabolism to cholesterol gallstone formation are unknown, but our knowledge is rapidly expanding. Systemic genomewide scans in mice from experimental crosses of inbred mouse strains have mapped the "Lith" loci to increased gallstone susceptibility (3,4). A growing number of genetic variants in some of these genes have been linked to human gallstone disease (10).…”

Reduced Susceptibility to Cholesterol Gallstone Formation in Mice That Do Not Produce Apolipoprotein B48 in the Intestine *

“…On chow, the APO-B100 deficiency in S tudies in humans and inbred mice have demonstrated that a complex genetic basis determines the individual and strain predisposition to develop cholesterol gallstones in response to environmental factors. 1 The primary pathophysiological defect involved in cholesterol gallstone formation is increased biliary secretion of cholesterol from the liver, which produces bile supersaturated with cholesterol. 2 Subsequently, biliary cholesterol precipitates as "anhydrous" and monohydrate crystals, which grow and agglomerate toward the formation of macroscopic stones in the gallbladder.…”

“…1 The primary pathophysiological defect involved in cholesterol gallstone formation is increased biliary secretion of cholesterol from the liver, which produces bile supersaturated with cholesterol. 2 Subsequently, biliary cholesterol precipitates as "anhydrous" and monohydrate crystals, which grow and agglomerate toward the formation of macroscopic stones in the gallbladder.…”