Mouse models of gallstone disease

Abstract

Purpose of review: The establishment of mouse models of gallstones, and the contribution of mouse models to genetic studies of gallstone disease, as well as the latest advances in the pathophysiology of gallstones from mouse experiments are summarized.

Recent findings: The combined uses of genomic strategies and phenotypic studies in mice have successfully led to the identification of many Lith genes, which pave the way for the discovery of human LITH genes. The physical-chemical, genetic, and molecular biological studies of gallstone disease in mice with knockout or transgene of specific target genes have provided many novel insights into the complex pathophysiological mechanisms of this very common hepatobiliary disease worldwide, showing that interactions of five primary defects play a critical role in the pathogenesis of cholesterol gallstones. Based on mouse studies, a new concept has been proposed that hepatic hypersecretion of biliary cholesterol is induced by multiple Lith genes, with insulin resistance as part of the metabolic syndrome interacting with cholelithogenic environmental factors to cause the phenotype.

Summary: The mouse model of gallstones is crucial for elucidating the physical-chemical and genetic mechanisms of cholesterol crystallization and gallstone formation, which greatly increase our understanding of the pathogenesis of this disease in humans.

FIGURE 1

Representative photomicrographs of cholesterol crystallization and gallstone formation observed by phase contrast and polarizing light microscopy in gallbladder bile of gallstone-susceptible C57L/J mice during the 8-week period of feeding a lithogenic diet: (a) mucin gel; (b) small liquid crystals; (c) aggregated liquid crystals; (d) fused liquid crystals with Maltese-cross birefringence and focal conic textures; (e) arc-like (possible anhydrous cholesterol) crystal; (f) filamentous crystals; (g) tubular crystal fracturing at ends to produce cholesterol monohydrate crystals; (h) typical cholesterol monohydrate crystal, with 79.2° and 100.8° angles; (i) agglomerated cholesterol monohydrate crystals; (j and k) sandy stones; and (l) gallstones. Reproduced with permission from reference [13].

FIGURE 2

The gallstone (Lith) gene map shows the quantitative trait loci (QTL) regions containing Lith genes, as well as candidate genes for cholesterol gallstone disease on mouse chromosomes. A vertical line represents one chromosome, with the centromere at the top. Genetic distances from the centromere (horizontal black lines) are indicated to the left of the chromosomes in centimorgans (cM). The locations of gallstone QTLs (Lith genes) and candidate genes are indicated by horizontal black lines with the gene symbols to the right (see Table 1 for the list of gene symbols and names). Reproduced with permission from reference [31].

FIGURE 3

Interactions of five primary defects promote the formation of cholesterol gallstones: (i) genetic factors and Lith genes; (ii) hepatic hypersecretion; (iii) gallbladder hypomotility; (iv) rapid phase transitions; and (v) intestinal factors. Persistent hepatic cholesterol hypersecretion is the consequence of complex genetic predispositions, leading to the formation of cholesterol-supersaturated bile and accelerating cholesterol crystallization. Impaired gallbladder motility results in the production and accumulation of excess mucin gel, promoting the formation of biliary sludge and the growth of microlithiasis. These alterations also disrupt the kinetics of the enterohepatic circulation of bile acids (intestinal factors), leading to a diminished intestinal absorption and pool size of bile acids. Increased cholesterol absorption delivers dietary and re-absorbed biliary cholesterol to the liver for secretion into bile. Abnormal intestinal microbiota may disrupt cholesterol and bile acid metabolism in the liver, intestine, and bile, as well as impair gallbladder emptying and refilling. Reproduced with permission from reference [31].