scholarly journals New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice

2003 ◽  
Vol 14 (3) ◽  
pp. 225-239 ◽  
Author(s):  
Malcolm A. Lyons ◽  
Henning Wittenburg ◽  
Renhua Li ◽  
Kenneth A. Walsh ◽  
Monika R. Leonard ◽  
...  
Keyword(s):  
Quantitative Trait ◽  
Cholesterol Gallstone ◽  
Inbred Mice ◽  
Gallstone Formation ◽  
Preliminary Evaluation ◽  
Lithogenic Diet ◽  
Genetic Complexity ◽  
Qtl Fine Mapping ◽  
Human Disorder ◽  
Trait Locus

Cholesterol gallstone formation is a response to interactions between multiple genes and environmental stimuli. To determine the subset of cholesterol gallstone susceptibility ( Lith) genes possessed by strains CAST/Ei (susceptible) and 129S1/SvImJ (resistant), we conducted quantitative trait locus (QTL) analyses of an intercross between these strains. Parental strains and F1 mice of both genders were evaluated for gallstone formation after consumption of a lithogenic diet for 8 wk. Gallstone susceptibility of strain CAST was predominantly due to cholesterol hypersecretion. Male intercross offspring were genotyped and phenotyped for cholesterol gallstone formation after consumption of the lithogenic diet for 10 wk. Linkage analysis was performed using PSEUDOMARKER software. One significant, new QTL was detected and named Lith13 [chromosome (Chr) 5, 30 cM]. Statistical analyses and QTL fine mapping suggest this QTL may comprise two closely linked loci. We confirmed the presence of Lith6 (Chr 6). Suggestive QTL were detected on Chrs 1, 2, 5, 14, and 16. The QTL on Chrs 2 and 16 confirmed previously identified, suggestive QTL. Therefore, they were named Lith12 (101 cM) and Lith14 (42 cM), respectively. We identified candidate genes based on known function and location and performed mRNA expression analyses using both parental strains and intercross progeny for preliminary evaluation of their contributions to gallstone formation. Cebpb ( Lith12), Pparg ( Lith6), and Slc21a1 ( Lith6) displayed expression differences. Our work continues to demonstrate the genetic complexity and to elucidate the pathophysiology of cholesterol gallstone formation. It should facilitate the development of new approaches for treating this common human disorder.

scholarly journals Quantitative trait loci mapping for cholesterol gallstones in AKR/J and C57L/J strains of mice

2000 ◽  
Vol 4 (1) ◽  
pp. 59-65 ◽  
Author(s):  
BEVERLY PAIGEN ◽  
NICHOLAS J. SCHORK ◽  
KAREN L. SVENSON ◽  
YIN-CHAI CHEAH ◽  
JIAN-LONG MU ◽  
...  
Keyword(s):  
Quantitative Trait ◽  
Congenic Strain ◽  
Cholesterol Gallstone ◽  
Gallstone Disease ◽  
Gallstone Formation ◽  
Quantitative Trait Loci Mapping ◽  
Cholesterol Gallstones ◽  
Lithogenic Diet ◽  
The Difference ◽  
Trait Locus

Quantitative trait locus (QTL) mapping was used to locate genes that determine the difference in cholesterol gallstone disease between the gallstone-susceptible strain C57L/J and the gallstone-resistant strain AKR/J. Gallstone weight was determined in 231 male (AKR × C57L) F1× AKR backcross mice fed a lithogenic diet containing 1% cholesterol, 0.5% cholic acid, and 15% butterfat for 8 wk. Mice having no stones and mice having the largest stones were genotyped at ∼20-cM intervals to find the loci determining cholesterol gallstone formation. The major locus, Lith1, mapped near D2Mit56 and was confirmed by constructing a congenic strain, AK.L- Lith1s. Another locus, Lith2, mapped near D19Mit58 and was also confirmed by constructing a congenic strain AK.L- Lith2s. Other suggestive, but not statistically significant, loci mapped to chromosomes 6, 7, 8, 10, and X. The identification of these Lith genes will elucidate the pathophysiology of cholesterol gallstone formation.

FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice

2003 ◽  
Vol 125 (3) ◽  
pp. 868-881 ◽  
Author(s):  
Henning Wittenburg ◽  
Malcolm A. Lyons ◽  
Renhua Li ◽  
Gary A. Churchill ◽  
Martin C. Carey ◽  
...  
Keyword(s):  
Quantitative Trait Locus ◽  
Quantitative Trait Locus Mapping ◽  
Quantitative Trait ◽  
Cholesterol Gallstone ◽  
Gallstone Formation ◽  
Trait Locus ◽  
Locus Mapping

Quantitative Trait Locus Mapping for Ethanol Teratogenesis in BXD Recombinant Inbred Mice

2012 ◽  
Vol 36 (8) ◽  
pp. 1340-1354 ◽  
Author(s):  
Chris Downing ◽  
Christina Balderrama-Durbin ◽  
Alexi Kimball ◽  
Jami Biers ◽  
Hali Wright ◽  
...  
Keyword(s):  
Quantitative Trait Locus ◽  
Quantitative Trait Locus Mapping ◽  
Quantitative Trait ◽  
Recombinant Inbred ◽  
Inbred Mice ◽  
Recombinant Inbred Mice ◽  
Trait Locus ◽  
Locus Mapping

scholarly journals Protective Effects of Yinchenhao Decoction on Cholesterol Gallstone in Mice Fed a Lithogenic Diet by Regulating LXR, CYP7A1, CYP7B1, and HMGCR Pathways

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Yong Meng ◽  
Ke Meng ◽  
Xin Zhao ◽  
Donghua Li ◽  
Qiaoying Gao ◽  
...  
Keyword(s):  
Cholesterol Gallstone ◽  
Saturation Index ◽  
Gallstone Formation ◽  
Intragastric Administration ◽  
Protective Effects ◽  
Biochemical Tests ◽  
Lithogenic Diet ◽  
Preventive Drug ◽  
Cholesterol Saturation Index ◽  
Bile Cholesterol

The study attempted to elucidate whether lipid genes are closely associated with lipid metabolic abnormalities during the lithogenic time and how Yinchenhao Decoction (YCHD) works on the transcriptions of lipid genes against cholesterol gallstone model. C57BL/6J mice fed on lithogenic diet (LD) were used for model establishment and randomized into 5 groups. All groups received LD for different weeks with isometrically intragastric administration of YCHD or NS. Biochemical tests were measured and liver tissues were harvested for histological and genetic detection. It was found that all groups with increasing LD showed a following tendency of gallstone incidence, bile cholesterol, phospholipids, total bile acid, and cholesterol saturation index (CSI). Conversely, YCHD could significantly normalize the levels of gallstone incidence, bile lipids, and CSI (CSI<1). As lithogenic time progressed, ABCG5, ABCG8, PPAR-α, and ABCB4 were upregulated, and SREBP2, CYP7A1, and CYP7B1 were downregulated, while CYP7A1, CYP7B1, LXR, and HMGCR mRNA were increased 3-fold under the administration of YCHD. It was concluded that abnormal expressions of the mentioned genes may eventually progress to cholesterol gallstone. CYP7A1, CYP7B1, LXR, and HMGCR mRNA may be efficient targets of YCHD, which may be a preventive drug to reverse liver injury, normalize bile lipids, facilitate gallstone dissolution, and attenuate gallstone formation.

scholarly journals Sterol carrier protein 2 participates in hypersecretion of biliary cholesterol during gallstone formation in genetically gallstone-susceptible mice

1998 ◽  
Vol 336 (1) ◽  
pp. 33-37 ◽  
Author(s):  
Michael FUCHS ◽  
Frank LAMMERT ◽  
David Q.-H. WANG ◽  
Beverly PAIGEN ◽  
Martin C. CAREY ◽  
...  
Keyword(s):  
Steady State ◽  
Cholesterol Gallstone ◽  
Gallstone Formation ◽  
Carrier Protein ◽  
Mrna Levels ◽  
Sterol Carrier Protein ◽  
Biliary Cholesterol ◽  
Lithogenic Diet ◽  
Sterol Carrier Protein 2 ◽  
Akr Mice

In inbred mice, susceptibility to cholesterol gallstone disease is conferred by Lith genes, which in part promote hypersecretion of cholesterol into bile in response to a high-fat/cholesterol/cholic acid (lithogenic) diet. Because cytosolic sterol carrier protein 2 (SCP2) is believed to participate in cellular cholesterol trafficking and is elevated in the liver cytosol of cholesterol gallstone patients, we defined the hepatic expression of SCP2 during cholesterol gallstone formation in gallstone-susceptible C57L and gallstone-resistant AKR mice fed the lithogenic diet. Steady-state cytosolic SCP2 levels in C57L, but not AKR mice increased as a function of time and were correlated positively with biliary cholesterol hypersecretion, cholesterol saturation indices of gall-bladder biles and the appearance of liquid and solid cholesterol crystals leading to gallstone formation. Steady-state mRNA levels increased co-ordinately, consistent with regulation of SCP2 expression at the transcriptional level. Our results suggest that overexpression of SCP2 contributes to biliary cholesterol hypersecretion and the pathogenesis of gallstones in genetically susceptible mice. Because of the different chromosomal localizations of the Lith and Scp2 genes, we postulate that Lith genes control SCP2 expression indirectly.

Gallbladder prostaglandins and lysophospholipids as mediators of mucin secretion during cholelithiasis

1986 ◽  
Vol 251 (5) ◽  
pp. G701-G709 ◽  
Author(s):  
W. W. LaMorte ◽  
J. T. LaMont ◽  
W. Hale ◽  
M. L. Booker ◽  
T. E. Scott ◽  
...  
Keyword(s):  
Cholesterol Gallstone ◽  
Early Stage ◽  
Gallstone Formation ◽  
Prairie Dogs ◽  
Crystal Formation ◽  
Cholesterol Feeding ◽  
Culture Studies ◽  
Gallbladder Mucosa ◽  
Lithogenic Diet ◽  
Dose Dependent

Mucin hypersecretion from the gallbladder epithelium contributes to cholesterol gallstone formation by accelerating the nucleation of cholesterol-supersaturated bile. Prostaglandins (PGs) and lysophosphatidylcholine (LPC) have both been implicated as potential mediators of mucin hypersecretion, but their roles are unclear. We fed prairie dogs a lithogenic diet (0.34% cholesterol), and after 1, 2, 4, or 6 wk of cholesterol feeding, we measured glycoprotein and LPC concentrations in bile and PG synthesis in gallbladder and liver slices. Hypercholesterolemia and cholesterol supersaturation of bile occurred after 1 wk of cholesterol feeding, but marked crystal formation was delayed until 4 wk, when glycoprotein concentrations became markedly elevated. Glycoprotein hypersecretion was preceded by increased synthesis of PGF2 alpha (P less than 0.002), PGE2 (P less than 0.001), prostacyclin (P less than 0.05), and thromboxane (P = 0.07) in the gallbladder after only 2 wk of cholesterol feeding, but PG synthesis in the liver remained unchanged (P greater than 0.14). LPC concentrations in gallbladder bile also increased at 2 wk (P less than 0.02), but LPC in hepatic bile was unchanged (P = 0.35). In organ culture studies, LPC caused a dose-dependent stimulation of [3H]glycoprotein release from guinea pig gallbladder mucosa that could not be explained solely by LPC's detergent properties. We conclude that gallbladder PG synthesis and LPC production are increased at an early stage of cholesterol gallstone formation in the prairie dog model. These changes probably play a significant role in gallstone pathogenesis, since they mediate hypersecretion of gallbladder mucin and thus favor the nucleation of cholesterol-supersaturated bile.

Quantitative trait locus analysis of susceptibility to diet-induced atherosclerosis in recombinant inbred mice

1994 ◽  
Vol 32 (11-12) ◽  
pp. 397-407 ◽  
Author(s):  
Richard W. Hyman ◽  
Susan Frank ◽  
Craig H. Warden ◽  
Aaron Daluiski ◽  
Renu Heller ◽  
...  
Keyword(s):  
Quantitative Trait Locus ◽  
Quantitative Trait Locus Analysis ◽  
Quantitative Trait ◽  
Recombinant Inbred ◽  
Inbred Mice ◽  
Recombinant Inbred Mice ◽  
Trait Locus

scholarly journals Inbreeding and the Genetic Complexity of Human Hypertension

Genetics ◽  
2003 ◽  
Vol 163 (3) ◽  
pp. 1011-1021 ◽  
Author(s):  
Igor Rudan ◽  
Nina Smolej-Narancic ◽  
Harry Campbell ◽  
Andrew Carothers ◽  
Alan Wright ◽  
...  
Keyword(s):  
Quantitative Trait ◽  
Genetic Architecture ◽  
Late Onset ◽  
Human Hypertension ◽  
Considerable Uncertainty ◽  
Global Impact ◽  
Genetic Complexity ◽  
Trait Locus ◽  
Dominance Variation ◽  
Strong Linear Relationship

Abstract Considerable uncertainty exists regarding the genetic architecture underlying common late-onset human diseases. In particular, the contribution of deleterious recessive alleles has been predicted to be greater for late-onset than for early-onset traits. We have investigated the contribution of recessive alleles to human hypertension by examining the effects of inbreeding on blood pressure (BP) as a quantitative trait in 2760 adult individuals from 25 villages within Croatian island isolates. We found a strong linear relationship between the inbreeding coefficient (F) and both systolic and diastolic BP, indicating that recessive or partially recessive quantitative trait locus (QTL) alleles account for 10-15% of the total variation in BP in this population. An increase in F of 0.01 corresponded to an increase of ∼3 mm Hg in systolic and 2 mm Hg in diastolic BP. Regression of F on BP indicated that at least several hundred (300-600) recessive QTL contribute to BP variability. A model of the distribution of locus effects suggests that the 8-16 QTL of largest effect together account for a maximum of 25% of the dominance variation, while the remaining 75% of the variation is mediated by QTL of very small effect, unlikely to be detectable using current technologies and sample sizes. We infer that recent inbreeding accounts for 36% of all hypertension in this population. The global impact of inbreeding on hypertension may be substantial since, although inbreeding is declining in Western societies, an estimated 1 billion people globally show rates of consanguineous marriages &gt;20%.

Helicobacter pyloriand cholesterol gallstone formation in C57L/J mice: a prospective study

2006 ◽  
Vol 290 (1) ◽  
pp. G175-G182 ◽  
Author(s):  
Kirk J. Maurer ◽  
Arlin B. Rogers ◽  
Zhongming Ge ◽  
Ashley J. Wiese ◽  
Martin C. Carey ◽  
...  
Keyword(s):  
Prospective Study ◽  
Cholesterol Gallstone ◽  
Stone Formation ◽  
Gallstone Formation ◽  
Crystal Formation ◽  
Lithogenic Diet ◽  
The Common ◽  
Cholesterol Monohydrate ◽  
H Pylori ◽  
A Prospective Study

Recently, we demonstrated that cholesterol gallstone-prone C57L/J mice rarely develop gallstones unless they are infected with certain cholelithogenic enterohepatic Helicobacter species. Because the common gastric pathogen H. pylori has been identified in the hepatobiliary tree of cholesterol gallstone patients, we wanted to ascertain if H. pylori is cholelithogenic, by prospectively studying C57L infected mice fed a lithogenic diet. Weanling, Helicobacter spp.-free male C57L mice were either infected with H. pylori SS1 or sham dosed. Mice were then fed a lithogenic diet (1.0% cholesterol, 0.5% cholic acid, and 15% dairy triglycerides) for 8 wk. At 16 wk of age, mice were euthanatized, the biliary phenotype was analyzed microscopically, and tissues were analyzed histopathologically. H. pylori infection did not promote cholesterol monohydrate crystal formation (20% vs. 10%), sandy stone formation (0% for both), or true gallstone formation (20%) compared with uninfected mice fed the lithogenic diet (10%). Additionally, H. pylori failed to stimulate mucin gel accumulation in the gallbladder or alter gallbladder size compared with uninfected animals. 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. We conclude that H. pylori infection does not play any role in murine cholesterol gallstone formation. Nonetheless, the C57L mouse develops severe lesions of both the glandular and nonglandular stomach in response to H. pylori infection and the lithogenic diet, respectively.

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