Disease relevance of Lith1

• After 12 wk of feeding the mice a lithogenic diet, we phenotyped 330 backcross progeny for gallstones, gallbladder mucin accumulation, liver weight, and body weight [1].
• Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile [2].
• METHODS: Helicobacter spp-free adult male C57L mice were infected with several different enterohepatic Helicobacter spp or left uninfected and fed either a lithogenic diet or standard mouse chow for 8 and 18 weeks [3].
• These data suggest that despite the lithogenic diet, endogenous sources constitute a significant proportion of biliary cholesterol during leptin-induced weight loss [4].
• H. pylori-infected C57L mice developed moderate to severe gastritis by 12 wk, and the lithogenic diet itself produced lesions in the forestomach, which were exacerbated by the infection [5].

Psychiatry related information on Lith1

• The critical period for gallstone formation produced by the lithogenic diet was one to two weeks after the start of the lithogenic diet [6].

High impact information on Lith1

• Analysis of mice on either the chow or the lithogenic diet revealed that CCK-1R(-/-) animals had larger gallbladder volumes (predisposing to bile stasis), significant retardation of small-intestinal transit times (resulting in increased cholesterol absorption), and increased biliary cholesterol secretion rates [7].
• We measured several parameters of cholesterol metabolism, fatty acid synthesis, and biliary lipid levels in mice fed a normal or a lithogenic diet [8].
• The incidence of gallstones decreased from 90% in control mice to 33% in Mttp(Delta/Delta) mice after 8 weeks of a lithogenic diet (P < .0001) [8].
• Quantitative trait locus (QTL) mapping was employed to identify Lith loci in mice [9].
• Because mouse and human genomes are conserved and only a critical subset of homologous genes appears rate limiting for gallstone susceptibility in these species, a genetic map of mouse lithogenic (Lith) loci provides a "roadmap" for the discovery of human LITH genes [9].

Chemical compound and disease context of Lith1

• In response to the lithogenic diet, activities of the regulatory enzymes in the two bile salt synthetic pathways are coordinately down-regulated and correlate inversely with prevalence rates of cholesterol crystals and gallstones [10].
• METHODS: To investigate molecular mechanisms of how estrogen influences cholesterol gallstones, we studied gonadectomized AKR/J mice of both genders that were implanted subcutaneously with pellets releasing 17beta-estradiol at 0, 3, or 6 microg/day and that were fed a lithogenic diet for 12 weeks [11].
• METHODS: We determined gall stone phenotype, HMGR activity, biliary lipid secretion rates, and counterregulatory events in male C57L/J mice and gall stone resistant AKR treated with Tu 2208 (30-60 mg/kg/day) or Ro 48-8071 (30-100 mg/kg/day), while ingesting chow or the lithogenic diet [12].
• When 0.25% ursocholic acid or ursodeoxycholic acid was added to the lithogenic diet, the incidence as well as the grade (severity) of the gallstones were reduced [13].
• These data suggest that ileectomy prevents the formation of cholesterol gallstones after the feeding of a lithogenic diet due to a decrease in cholic acid absorption [14].

Biological context of Lith1

• A major gene, named Lith1, mapped to mouse chromosome 2 [15].
• Our study defines the physical-chemical phenotypes of C57L, AKR, and (C57L x AKR) F1 mouse gallbladder biles during 56 days on the lithogenic diet [2].
• Three hundred twenty-four F2 offspring were phenotyped for cholelithiasis during consumption of a lithogenic diet and genotyped using microsatellite markers [16].
• 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 [17].
• In response to the lithogenic diet, fatty-acid binding protein of liver (FABPL) was markedly induced in both mouse strains [18].

Anatomical context of Lith1

• In studies on experimental lithiasis cell proliferation appeared to be enhanced in the gallbladder epithelium of mice fed on a cholesterol-cholic acid-rich lithogenic diet [19].
• Morphological alterations in epithelial cells of the mouse gallbladder 30 hours after treatment with lithogenic diet [20].
• Other prominent features of hepatocytes after lithogenic diet include segregation of nucleolar granular and fibrillar material [21].
• Animals fed a lithogenic diet for one month showed a marked increase of radioactive label mainly in cells of crypts and invaginations of the mouse gallbaldder mucosa [22].
• Gallstones were found in the gall-bladder and/or bile duct after feeding on a lithogenic diet for two weeks or more [6].

Associations of Lith1 with chemical compounds

• Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice [15].
• Abcb11 transgenic mice fed a lithogenic (high cholesterol/fat/cholic acid) diet display markedly reduced hepatic steatosis compared with wild-type controls [23].
• RESULTS: 17beta-estradiol promoted gallstone formation by up-regulating hepatic expression of ERalpha but not ERbeta, and the lithogenic actions of estrogen can be blocked completely by the antiestrogenic ICI 182,780 [11].
• The incidence of gallstone formation in the mouse by the addition of 2.5% sitosterol in the lithogenic diet is about 35.5% in male and 25% in female [24].
• Together, these changes lead to increased DCA formation, solubilization and absorption, Thus, in addition to the 'lithogenic liver' and 'guilty gall-bladder' one must now add the 'indolent intestine' to the list of culprits in cholesterol gallstone formation [25].

Regulatory relationships of Lith1

• TTR-Abcb11 and FVB/NJ strain control mice were fed a lithogenic or chow diet and cholesterol crystal and gallstone formation were measured [26].
• In inbred mice gallstone susceptibility is determined by Lith (lithogenic) genes which promote cholesterol hypersecretion in bile as a response to a high-fat diet [27].
• HL knockout mice had a similar prevalence of gallstone formation as compared with control mice when both strains were fed with a lithogenic diet [28].

Other interactions of Lith1

• In response to the lithogenic diet, Bsep (Abcb11) protein expression was up-regulated only marginally and bile salt secretion did not increase [29].
• 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 [15].
• In response to the lithogenic diet, a greater reduction in cholesterol 7alpha-hydroxylase activity in Pctp-/- mice could be attributed to increased size and hydrophobicity of the bile salt pool [30].
• Basal expression of hepatic SR-BI protein was dissimilar in both wild-type and SR-BI mice, and remained unaltered in response to the lithogenic diet [31].
• Male agouti mice of the same age did not form gallstones until they had consumed the lithogenic food for 8 weeks [32].

Analytical, diagnostic and therapeutic context of Lith1

• After 12 weeks of feeding the lithogenic diet to inbred mice of strains A/J and AKR/J as well as their F(1) progeny, we used microscopy of bile to assess mucin accumulation, crystallization pathways, and stone formation [33].
• The morphological changes were identical in animals subjected to truncal vagotomy and given a lithogenic diet [34].
• Animal studies revealed that Aramchol was absorbed after oral administration and could prevent cholesterol crystallization as well as dissolve preformed crystals in rodents fed a lithogenic diet [35].
• For this purpose, the hepatic biles of rats fed a control, lithogenic, and lithogenic diet supplemented with curcumin or capsaicin were subjected to gel filtration chromatography (sepharose-4B-Cl) and the LMW protein fractions were tested for their ability to influence cholesterol crystal growth in model bile [36].

References