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.

A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice

“…As found by clinical and epidemiological studies, the prevalence of cholesterol gallstone disease in women is twice that of men (24), and oral contraceptives or other estrogen therapies significantly increase that risk (26). Although the classical ER critical role in estrogeninduced lithogenic effects, genetic studies have found that Gper1 is a new gallstone gene, Lith18, in mice (31) and is also involved in estrogen-dependent lithogenic pathways (29,50). In a mouse model of E2-induced gallstones, CIMBA reduces gallstone formation in a dose-dependent manner in OVX mice.…”

“…Although plays a key role in estrogen's lithogenic effects (28), new evidence has shown that GPER can , to promote gallstone formation in female mice (29,30). More importantly, genetic analysis has found that Gper1 is a new gallstone gene, Lith18, on chromosome 5 in mice (31). All these studies strongly suggested that GPER could play a critical role in the formation of estrogeninduced cholesterol gallstones (32).…”

Advances in Research on the Pathogenesis of Type 2 Diabetes Complicated with Gallstone

“…The immediate cause of insulin resistance has not been fully established, but long-term hyperglycemia and hyperinsulinemia are known to cause insulin resistance in human and animal models [9] [10]. In the study of the LIRKO mouse model, the incidence of gallstones in mice was significantly increased after disrupting the intrahepatic insulin receptor in mice [11].…”

Depletion of hepatic forkhead box O1 does not affect cholelithiasis in male and female mice

“…In this context, a preclinical study by Biddinger et al (44) reports that hepatic insulin resistance directly promotes the formation of gallstones in mice, when fed a lithogenic diet (LD) -a dietary regimen that is shown to stimulate gallstone formation in a number of animal models (45,46). They show that mice with conditional insulin receptor (Ir) depletion in the liver develop gallstone disease, as result of genetically inherited insulin resistance in Ir-knockout mice (44).…”

“…Liver-conditional FoxO1knockout mice vs. age/sex-matched wild-type littermates were fed on LD, followed by the determination of the effect of hepatic FoxO1 depletion on bile acid metabolism and gallstone disease. To corroborate these studies, we developed a high fatcontaining lithogenic diet (HFLD) with 60% fat content, as the low fat content (15% fat) in LD is inadequate to induce obesity (45,46). We replicated our studies by feeding liver-conditional FoxO1-knockout mice vs. age/sex-matched wild-type littermates the newly customized HFLD to further test our hypothesis that FoxO1 deregulation, resulting from overnutrition and insulin resistance, is culpable for the pathogenesis of cholelithiasis in obesity.…”