Different susceptibilities to the formation of cholesterol gallstones in mice

Alexander, Manfred; Portman, Oscar W.

doi:10.1002/hep.1840070209

Cited by 30 publications

(15 citation statements)

References 26 publications

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“…Later, Fujihira et al [61] found that prevalence of cholesterol gallstones varied from 0% to 100% among six strains of mice. Alexander and Portman [62] observed that, upon being fed the lithogenic diet, C57BL/6 mice were susceptible to gallstone formation, whereas CBA mice were resistant. Recently, Khanuja et al [63••] studied nine inbred strains of mice on the lithogenic diet for 12 weeks and found that differences in gallstone susceptibility between C57L/J and AKR/J strains were determined by at least two Lith genes with Lith1 (for lithogenic gene 1) mapping to mouse chromosome 2 by QTL analysis.…”

Section: Quantitative Trait Locus Study and Lith (Gallstone) Genes Inmentioning

confidence: 98%

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

Wang

Afdhal

2004

Curr Gastroenterol Rep

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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.

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Section: Quantitative Trait Locus Study and Lith (Gallstone) Genes Inmentioning

confidence: 98%

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

Wang

Afdhal

2004

Curr Gastroenterol Rep

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“…This diet is known to cause gallstone formation and accumulation of fat in mouse liver (Alexander and Portman, 1987;Nishina et al, 1990). We focused on comparing K8-null with heterozygous and WT mice given that K8-null mice had the most significant keratin alterations in the gallbladder (Figs 2, 3) and liver (Baribault et al, 1994;Caulin et al, 2000;Gilbert et al, 2001;Loranger et al, 1997;Toivola et al, 1998;Toivola et al, 2001;Zatloukal et al, 2000).…”

Section: Effect Of a Lithogenic Diet On Gallbladder And Liver Injury mentioning

confidence: 99%

“…We focused on comparing K8-null with heterozygous and WT mice given that K8-null mice had the most significant keratin alterations in the gallbladder (Figs 2, 3) and liver (Baribault et al, 1994;Caulin et al, 2000;Gilbert et al, 2001;Loranger et al, 1997;Toivola et al, 1998;Toivola et al, 2001;Zatloukal et al, 2000). We used a feeding period of 5 weeks based on the known frequency of mouse gallstone formation (~50-60%) among different mouse strains (though there are significant strain and sex related differences) (Alexander and Portman, 1987;Nishina et al, 1990). As shown in Table 2, the incidence of gallstone formation is similar among the three K8 mouse genotypes, and hence is independent of gallbladder keratin expression level or filament organization.…”

Section: Effect Of a Lithogenic Diet On Gallbladder And Liver Injury mentioning

confidence: 99%

Keratin-8 null mice have different gallbladder and liver susceptibility to lithogenic diet-induced injury

Guo

Toivola

Zhong

et al. 2003

Journal of Cell Science

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Keratin transgenic mouse models and the association of human keratin mutations with liver disease highlight the importance of keratins in protecting the liver from environmental insults, but little is known regarding keratins and their function in the gallbladder. We characterized keratin expression pattern and filament organization in normal and keratin polypeptide-8 (K8)-null, K18-null and K19-null gallbladders, and examined susceptibility to liver and gallbladder injury induced by a high-fat lithogenic diet (LD) in K8-null mice. The major keratins of normal mouse gallbladder are K8>K19>K18 which become markedly depleted in K8-null mice with minor K18/K19 remnants and limited K7 over-expression. Compensatory K18/K20 protein and RNA overexpression occur in K19-null but not in K18-null gallbladders, probably because of the higher levels of K19 than K18 in normal gallbladder. LD challenge causes more severe liver injury in K8-null than wild-type mice without altering keratin protein levels. In contrast, wild-type and K8-null gallbladders are equally susceptible to LD-induced injury and stone formation, but wild-type gallbladders do overexpress keratins upon LD challenge. LD-induced injury triggers keratin hyperphosphorylation in wild-type livers and gallbladders. Hence, mouse gallbladder K8/K18/K19 expression is induced in response to cholelithiasis injury. A high-fat LD increases the susceptibility of K8-null mice to liver but not gallbladder injury, which suggests that keratin mutations may increase the risk of liver damage in patients with steatohepatitis. Differences between K8-null mouse gallbladder and hepatocyte susceptibility to injury may be related to their minimal versus absent keratin expression, respectively.

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“…Among studies of gallstone formation in animals, Alexander and Portman (4) demonstrated that C57BL/6 mice are susceptible to cholelithiasis, but CBA mice are resistant. In both strains bile was supersaturated with cholesterol but not to the same degree (4). Fujihara et al (5) reported that the prevalence of gallstones varied from 0% to 100% among six strains of laboratory mice.…”

mentioning

confidence: 99%

Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice.

Khanuja

Cheah

Hunt

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

189

170

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The prevalence of cholesterol gallstones differs among inbred strains of mice fed a diet containing 15% (wt/wt) dairy fat, 1% (wt/wt) cholesterol, and 0.5% (wt/wt) cholic acid. Strains C57L, SWR, and A were notable for a high prevalence of cholelithiasis; strains C57BL/6, C3H, and SJL had an intermediate prevalence; and strains SM, AKR, and DBA/2 exhibited no cholelithiasis after consuming the diet for 18 weeks. Genetic analysis of the difference in gallstone prevalence rates between strains AKR and C57L was carried out by using the AKXL recombinant inbred strain set and (AKR x C57L)F1 x AKR backcross mice. Susceptibility to gallstone formation was found to be a dominant trait determined by at least two genes. A major gene, named Lithl, mapped to mouse chromosome 2. When examined after 6 weeks on the lithogenic diet, the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.88) was downregulated as expected in the gallstone-resistant strains, AKR and SJL, but this enzyme failed to downregulate in C57L and SWR, the gallstone-susceptible strains. This suggests that regulation of the rate-limiting enzyme in cholesterol biosynthesis may be pivotal in determining the occurrence and severity of cholesterol hypersecretion and hence lithogenicity of gallbladder bile. These studies indicate that genetic factors are critical in determining gallstone formation and that the genetic resources of the mouse model may permit these factors to be identified.Both atherosclerosis and cholelithiasis result from excess cholesterol; in the one case cholesterol is deposited in arterial walls, and in the other case cholesterol precipitates in the gallbladder. Both diseases are prevalent in cultures consuming a Western diet, and both can be induced in animal models by a diet high in cholesterol (1,2). In Western cultures, heart disease is the major cause of death, and gallstone disease is present in 10-40% of individuals over the age of 60 (3).Genetic factors apparently play an important role in the development of cholesterol gallstone disease. Among studies of gallstone formation in animals, Alexander and Portman (4) demonstrated that C57BL/6 mice are susceptible to cholelithiasis, but CBA mice are resistant. In both strains bile was supersaturated with cholesterol but not to the same degree (4). Fujihara et al. (5) reported that the prevalence of gallstones varied from 0% to 100% among six strains of laboratory mice.Evidence for the importance of genetic factors in human cholelithiasis is limited. Gallstone disease can be familial (6-11), and the bile from healthy sisters of female gallstone patients is more lithogenic than controls (11,12). In certain native populations of North and South America, a high percentage of adults develop cholesterol gallstones, suggesting common genetic factors (13,14).In previous studies, high fat plus high cholesterol diets produced atherosclerosis and gallstones in some strains of mice (15). In this report, we survey common inbred strains of mice for susceptibility to cholelith...

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Different susceptibilities to the formation of cholesterol gallstones in mice

Cited by 30 publications

References 26 publications

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

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

Keratin-8 null mice have different gallbladder and liver susceptibility to lithogenic diet-induced injury

Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice.

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