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.

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 The Role of Diet in the Pathogenesis of Cholesterol Gallstones

2019 ◽  
Vol 26 (19) ◽  
pp. 3620-3638 ◽  
Author(s):  
Agostino Di Ciaula ◽  
Gabriella Garruti ◽  
Gema Frühbeck ◽  
Maria De Angelis ◽  
Ornella de Bari ◽  
...  
Keyword(s):  
Vitamin C ◽  
Fast Food ◽  
Cholesterol Gallstone ◽  
Gallstone Disease ◽  
Gallstone Formation ◽  
Protective Role ◽  
Cholesterol Homeostasis ◽  
Major Health Problem ◽  
Cholesterol Gallstones ◽  
Beneficial Effects

: Cholesterol gallstone disease is a major health problem in Westernized countries and depends on a complex interplay between genetic factors, lifestyle and diet, acting on specific pathogenic mechanisms. Overweigh, obesity, dyslipidemia, insulin resistance and altered cholesterol homeostasis have been linked to increased gallstone occurrence, and several studies point to a number of specific nutrients as risk- or protective factors with respect to gallstone formation in humans. There is a rising interest in the identification of common and modifiable dietetic factors that put the patients at risk of gallstones or that are able to prevent gallstone formation and growth. In particular, dietary models characterized by increased energy intake with highly refined sugars and sweet foods, high fructose intake, low fiber contents, high fat, consumption of fast food and low vitamin C intake increase the risk of gallstone formation. On the other hand, high intake of monounsaturated fats and fiber, olive oil and fish (ω-3 fatty acids) consumption, vegetable protein intake, fruit, coffee, moderate alcohol consumption and vitamin C supplementation exert a protective role. : The effect of some confounding factors (e.g., physical activity) cannot be ruled out, but general recommendations about the multiple beneficial effects of diet on cholesterol gallstones must be kept in mind, in particular in groups at high risk of gallstone formation.

Fenugreek seeds reduce atherogenic diet-induced cholesterol gallstone formation in experimental mice

2009 ◽  
Vol 87 (11) ◽  
pp. 933-943 ◽  
Author(s):  
R.L.R. Reddy ◽  
K. Srinivasan
Keyword(s):  
Cholesterol Metabolism ◽  
Cholesterol Gallstone ◽  
Saturation Index ◽  
Gallstone Formation ◽  
Atherogenic Diet ◽  
High Cholesterol ◽  
Cholesterol Gallstones ◽  
Lithogenic Diet ◽  
Fenugreek Seed ◽  
Cholesterol Saturation Index

Dietary hypocholesterolemic adjuncts may have a beneficial role in the prevention and treatment of cholesterol gallstones (CGS). In this investigation, fenugreek (Trigonella foenum-graecum) seed was evaluated for this potential on the experimental induction of CGS in laboratory mice. CGS was induced by maintaining mice on a lithogenic diet (0.5% cholesterol) for 10 weeks. Fenugreek seed powder was included at 5%, 10%, and 15% of this lithogenic diet. Dietary fenugreek significantly lowered the incidence of CGS in these mice; the incidence was 63%, 40%, and 10% in the 5%, 10%, and 15% fenugreek groups, respectively, compared with 100% in the lithogenic control. The antilithogenic influence of fenugreek is attributable to its hypocholesterolemic effect. Serum cholesterol level was decreased by 26%–31% by dietary fenugreek, while hepatic cholesterol was lowered by 47%–64% in these high cholesterol-fed animals. Biliary cholesterol was 8.73–11.2 mmol/L as a result of dietary fenugreek, compared with 33.6 mmol/L in high-cholesterol feeding without fenugreek. Cholesterol saturation index in bile was reduced to 0.77–0.99 in fenugreek treatments compared with 2.57 in the high-cholesterol group. Thus, fenugreek seed offers health-beneficial antilithogenic potential by virtue of its favourable influence on cholesterol metabolism.

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

2020 ◽  
Vol 61 (5) ◽  
pp. 767-777 ◽  
Author(s):  
Chelsea DeLeon ◽  
Helen H. Wang ◽  
Joseph Gunn ◽  
McKenna Wilhelm ◽  
Aidan Cole ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Cholesterol Gallstone ◽  
Gallstone Disease ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Cholesterol Gallstones ◽  
Female Mice ◽  
Lithogenic Diet ◽  
Ovariectomized Mice ◽  
17Β Estradiol

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (−/−) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.­

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

Complete and overlapping congenics proving the existence of a quantitative trait locus for blood pressure on Dahl rat chromosome 17

2005 ◽  
Vol 21 (1) ◽  
pp. 112-116 ◽  
Author(s):  
Myrian Grondin ◽  
Vasiliki Eliopoulos ◽  
Raphaelle Lambert ◽  
Yishu Deng ◽  
Anita Ariyarajah ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Congenic Strain ◽  
Chromosome 17 ◽  
Congenic Strains ◽  
Genome Wide ◽  
A Genome ◽  
Trait Locus ◽  
Negative Controls

Linkage studies suggested that a quantitative trait locus (QTL) for blood pressure (BP) was present in a region on chromosome 17 (Chr 17) of Dahl salt-sensitive (DSS) rats. A subsequent congenic strain targeting this QTL, however, could not confirm it. These conflicting results called into question the validity of localization of a QTL by linkage followed by the use of a congenic strain made with an incomplete chromosome coverage. To resolve this issue, we constructed five new congenic strains, designated C17S.L1 to C17S.L5, that completely spanned the ±2 LOD confidence interval supposedly containing the QTL. Each congenic strain was made by replacing a segment of the DSS rat by that of the normotensive Lewis (LEW) rat. The only section to be LL homozygous is the region on Chr 17 specified in a congenic strain, as evidenced by a total genome scan. The results showed that BPs of C17S.L1 and C17S.L2 were lower ( P < 0.04) than that of DSS rats. In contrast, BPs of C17S.L3, C17S.L4, and C17S.L5 were not different ( P > 0.6) from that of DSS rats. Consequently, a BP QTL must be located in an interval of ∼15 cM shared between C17S.L1 and C17S.L2 and unique to them both, as opposed to C17S.L3, C17S.L4, and C17S.L5. The present study illustrates the importance of thorough chromosome coverage, the necessity for a genome-wide screening, and the use of “negative” controls in physically mapping a QTL by congenic strains.

Two closely linked interactive blood pressure QTL on rat chromosome 5 defined using congenic Dahl rats

2002 ◽  
Vol 8 (2) ◽  
pp. 81-86 ◽  
Author(s):  
Michael R. Garrett ◽  
John P. Rapp
Keyword(s):  
Blood Pressure ◽  
Quantitative Trait Locus ◽  
Quantitative Trait ◽  
Congenic Strain ◽  
Major Effect ◽  
Large Region ◽  
Chromosome 5 ◽  
Low Blood Pressure ◽  
Trait Locus

Previously we reported the construction of a congenic strain, S.LEW( 5 ), spanning a large region of rat chromosome 5. The Lewis (LEW) strain was the donor, and the Dahl salt-sensitive (S) strain was the recipient. The congenic strain included a blood pressure quantitative trait locus (QTL). In the present work, a series of nine congenic substrains were constructed from S.LEW( 5 ) which defined two closely linked blood pressure QTL in the region previously thought to contain only one. LEW low-blood-pressure alleles at both QTL were required for a major effect on blood pressure. Neither LEW allele alone had a significant effect on blood pressure. The two QTL were localized to regions 6.3 and 4.6 cM, and these were 1.0 cM apart.

scholarly journals Molecular Mechanisms Underlying the Link between Nuclear Receptor Function and Cholesterol Gallstone Formation

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Mary Carmen Vázquez ◽  
Attilio Rigotti ◽  
Silvana Zanlungo
Keyword(s):  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Cholesterol Metabolism ◽  
Cholesterol Gallstone ◽  
Gallstone Disease ◽  
Gallstone Formation ◽  
Receptor Function ◽  
Prevalent Disease ◽  
Bile Cholesterol

Cholesterol gallstone disease is highly prevalent in western countries, particularly in women and some specific ethnic groups. The formation of water-insoluble cholesterol crystals is due to a misbalance between the three major lipids present in the bile: cholesterol, bile salts, and phospholipids. Many proteins implicated in biliary lipid secretion in the liver are regulated by several transcription factors, including nuclear receptors LXR and FXR. Human and murine genetic, physiological, pathophysiological, and pharmacological evidence is consistent with the relevance of these nuclear receptors in gallstone formation. In addition, there is emerging data that also suggests a role for estrogen receptor ESR1 in abnormal cholesterol metabolism leading to gallstone disease. A better comprehension of the role of nuclear receptor function in gallstone formation may help to design new and more effective therapeutic strategies for this highly prevalent disease condition.

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