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J Appl Physiol 104: 761-765, 2008. First published January 10, 2008; doi:10.1152/japplphysiol.01292.2007
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Endurance exercise training reduces gallstone development in mice

Kenneth R. Wilund,1,2 Laura A. Feeney,1 Emily J. Tomayko,2 Hae R. Chung,1 and Kijin Kim3

1Department of Kinesiology and Community Health and 2Division of Nutritional Sciences, University of Illinois, Urbana, Illinois; and 3Department of Physical Education, Keimyung University, Daegu, Korea

Submitted 6 December 2007 ; accepted in final form 6 January 2008


   ABSTRACT
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 ABSTRACT
METHODS
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 DISCUSSION
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Gallstones form when the ratio of bile cholesterol to bile acids and phospholipids is elevated, causing cholesterol to precipitate. Physical inactivity is hypothesized to increase gallstone development, but experimental evidence supporting this is lacking, and potential mechanisms for the antilithogenic effects of exercise have not been described. The purpose of this study was to examine the effect of endurance exercise training on gallstone formation and the expression of genes involved in bile cholesterol metabolism in gallstone-sensitive (C57L/J) mice. At 10 wk, 50 male mice began a lithogenic diet and were randomly assigned to an exercise-training (EX) or sedentary (SED) group (n = 25 per group). Mice in the EX group ran on a treadmill at ~15 m/min for 45 min/day for 12 wk. At the time animals were euthanized, gallstones were collected, pooled by group, and weighed. The weight of the gallstones was 2.5-fold greater in the SED mice compared with EX mice (143 vs. 57 mg, respectively). In the EX mice, hepatic expression of the low-density lipoprotein receptor (LDLr), scavenger receptor class B type 1 (SRB1), and sterol 27 hydroxylase (Cyp27) was increased by ~2-fold (P < 0.05 for each). The LDLr and SRB1 increase cholesterol clearance by low-density lipoprotein and high-density lipoprotein particles, respectively, while Cyp27 promotes the catabolism of cholesterol to bile acids. Taken together, these data indicate that exercise promotes changes in hepatic gene expression that increase cholesterol uptake by the liver but simultaneously increase the catabolism of cholesterol to bile acids, effectively reducing cholesterol saturation in the bile. This suggests a mechanism by which exercise improves cholesterol clearance from the circulation while simultaneously inhibiting gallstone formation.

cholesterol; bile; physical activity

GALLBLADDER DISEASE affects 10–25% of adults in the United States (8). It has the second highest direct cost of any digestive disease at $5.8 billion annually and results in over 800,000 hospitalizations per year (24). Cholesterol gallstones form when the ratio of cholesterol to bile acids and phospholipids exceeds critical levels, causing the cholesterol to precipitate in the bile (32). Known risk factors for gallstones include age, high energy intake, obesity, non-insulin-dependent diabetes, hyperlipidemia, rapid weight loss, female gender, and parity (7, 8).

Physical inactivity has been suggested to increase the risk of gallstones (29), but experimental evidence supporting this hypothesis is lacking. Several observational studies in humans have shown an inverse relationship between the prevalence of gallstones and physical activity levels (6, 16, 17, 20), although several others have not (2, 14). To date, there have been no longitudinal studies in humans or animals to directly examine the impact of endurance exercise training on gallstone development.

In addition, the mechanisms by which physical activity or exercise may influence biliary cholesterol and gallstone development are unclear. As obesity is a known risk factor for gallstone disease, exercise-mediated prevention of obesity and/or reduction in body weight may play a role. Exercise also has been shown to increase gastric emptying rates (30), which may improve the impaired gastrointestinal motility that often occurs in gallstone disease. Furthermore, physical activity could directly affect bile cholesterol solubility by altering the expression of genes or proteins involved in hepatic cholesterol, phospholipid, and bile acid synthesis or secretion into the bile, although this hypothesis has never been thoroughly examined.

Longitudinal exercise-training studies in appropriate animal models may help elucidate potential mechanisms by which physical activity could impact gallstone development. Several exercise training studies in rats have examined cholesterol metabolism in the liver and bile (11, 27, 34), but rats do not have gallbladders; therefore gallstone development studies are not possible in this model. Recently, it was discovered that certain inbred strains of mice rapidly form gallstones when placed on a high-fat diet supplemented with cholic acid (15). These gallstone-susceptible strains have been used to identify genetic contributions to gallstone disease (13) but not the impact of exercise training on gallstone formation. Therefore, we used a 12-wk exercise training intervention in a gallstone-susceptible mouse strain (C57L/J) to investigate if exercise would prevent or attenuate the development of gallstones in mice consuming a lithogenic diet. Furthermore, we examined the expression of several genes associated with hepatic cholesterol metabolism to elucidate potential mechanisms by which exercise might be impacting gallstone formation. We hypothesized that exercise training would attenuate gallstone formation in mice, possibly by modulating hepatic gene expression in ways that increase the solubilization of cholesterol in the bile.


   METHODS
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 METHODS
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Animals, diets, and exercise.   Fifty male C57L/J mice were used in this study. C57L/J (stock no. 000668) breeder pairs were purchased from Jackson Labs (Bar Harbor, ME) to establish a breeder colony. All animals were housed in plastic cages in a temperature-controlled room with 12:12-h light-dark cycles and provided ad libitum access to food and water.

All mice were weaned at 4 wk of age and placed on a standard chow diet. At 10 wk of age, all mice were weighed, had blood drawn from the retro-orbital vein after an overnight fast, and then randomly assigned to an exercise (EX) or sedentary (SED) group (n = 25 per group). All mice were then switched to a lithogenic "Paigen" diet (22), consisting of standard chow feed (Harlan Teklad, powder diet no. 8640) supplemented to a final concentration of 21% fat (using milk fat), 1.25% cholesterol, and 0.5% cholic acid. The EX mice began their 12 wk exercise training, which consisted of treadmill running 5 days/wk at approximately 12–15 m/min, gradually increasing to 45 min of running by the end of the first week. Past research has shown that this running speed corresponds to ~65% maximal oxygen uptake (VO2 max) in this strain of mice (25). After 12 wk, all mice were again weighed, had blood drawn from the retroorbital vein after an overnight fast, and then euthanized for tissue collection and analysis as described below. All experiments were approved by the University of Illinois at Urbana-Champaign Institutional Animal Care and Use Committee.

Plasma lipid analysis.   Plasma was collected by centrifugation from blood samples taken at baseline and death and frozen at –80°C until analyzed. Plasma cholesterol and triglyceride levels were measured by standard enzymatic methods using commercially available assay kits (Wako Chemicals, Richmond, VA).

Gallstone measurements.   At death, the gallbladders were removed from each animal and cut open to remove the gallstones. Due to the small size and low weight of the gallstones in many individual animals, stones from all animals in each group of mice (SED and EX) were pooled and weighed. The weight of the intact gallbladders (containing gallstones and bile) from individual animals was not recorded before removing the stones because it was evident that some of the gallbladders had recently contracted, so contained little bile. As a result, the weight of the intact gallbladders would not have been informative.

Gene expression analysis.   At death, the liver and intestine were removed and snap-frozen in liquid nitrogen until analyzed. Before freezing, the intestine was divided into three sections of equal length to represent the duodenum, jejunum, and ileum. The duodenum and jejunum are the primary sites of cholesterol absorption (19), so the ileum was discarded. RNA was isolated from liver, duodenum, and jejunum from 10 animals in each group using RNA-STAT 60 (Tel-test, Friendswood, TX). DNase treatment was performed using an RNAeasy mini kit (Qiagen, Turnberry, CA). Reverse transcription reactions were performed with 2 µg of RNA using TaqMan Reverse Transcription Reagents (Applied Biosystems, Foster City, CA). cDNA was stored at –20°C before analysis.

Real-time PCR was performed on an Mx3000P QPCR System (Stratagene, La Jolla, CA) using the Brilliant SYBR Green QPCR Master Mix (Stratagene, catalogue no. 600548). Primers used are as follows: cyclophilin, sense 5'-TGGAGAGCACCAAGACAGACA-3' and antisense 5'-TGCCGGAGTCGACAATGAT-3'; low-density lipoprotein receptor (LDLr), sense 5'-AGGCTGTGGGCTCCATAGG-3' and antisense 5'-TGCGGTCCAGGGTCATCT-3'; scavenger receptor class B type 1 (SRB1), sense 5'-TCCCCATGAACTGTTCTGTGGA-3' and antisense 5'-TGCCCGATGCCCTTGA-3'; ATP binding cassette transporter (ABC) G5, sense 5'-TGGATCCAACACCTCTATGCTAAA-3' and antisense 5'-GGCAGGTTTTCTCGATGAACTG-3'; ABCG8, sense 5'-TGCCCACCTTCCACATGTC-3' and antisense 5'-ATGAAGCCGGCAGTAAGGTAGA-3'; ABCB4, sense 5'-CTTGAGGCAGCGAGAAACG-3' and antisense 5'-GGTTGCTGATGCTGCCTAGTT-3'; Cyp7a1, sense 5'-AGCAACTAAACAACCTGCCAGTACTA-3' and antisense 5'-GTCCGGATATTCAAGGATGCA-3'; sterol 27 hydroxylase (Cyp27), sense 5'-GGAGGGCAAGTACCCAATAAGA-3' and antisense 5'-TGCGATGAAGATCCCATAGGT-3'; sterol 7-a hydroxylase (Cyp7a1), sense 5'-AGCAACTAAACAACCTGCCAGTACTA-3 and antisense 5'-GTCCGGATATTCAAGGATGCA-3'; 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase (HMGCR), sense 5'-CTTGTGGAATGCCTTGTGATTG-3' and antisense 5'-AGCCGAAGCAGCACATGAT-3'; HMG-CoA synthase (HMGCS), sense 5'-GCCGTGAACTGGGTCGAA-3' and antisense 5'-GCATATATAGCAATGTCTCCTGCAA-3'; ABCB11, sense 5'-AAGCTACATCTGCCTTAGACACAGAAA-3' and antisense 5'-CAATACAGGTCCGACCCTCTCT-3'; Niemann-Pick C1-Like 1 (NPC1L1), sense 5'-TGGACTGGAAGGACCATTTCC-3' and antisense 5'-CTCATAATGGTGCAGTTCTTGTTGT-3'. Reaction conditions for all primers were 95°C, 10 min, 1 cycle; 95°C, 30 s, 60°C, 1 min, 72°C, 1 min, 40 cycles.

The Mx3000P software was used to analyze real-time PCR results. Cyclophilin was used as the normalizing gene, and fold changes were calculated using the 2–{Delta}{Delta}CT method (18). The relative expression of each gene of interest in the SED group was arbitrarily set at 1.0.

Statistics.   All statistics were performed using SPSS version 12.0 (Chicago, IL). Independent samples t-tests were used to analyze group differences in all variables measured. All data are expressed as means ± SD. A P value of ≤0.05 was accepted as statistically significant. No statistical analysis was performed on the gallstone weights because only pooled sample weights were available.


   RESULTS
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Body weights and plasma lipids.   Body weights and plasma lipid levels for animals in the SED and EX groups are shown in Table 1. Body weight did not differ between the groups at baseline. However, mice in the EX group gained significantly less weight than SED mice during the intervention (6.7 ± 3.6 vs. 12.9 ± 5.6 g, P < 0.01), resulting in significant difference in body weights at death (P < 0.01). There were no significant differences in triglyceride levels between the groups at baseline or final testing. Plasma cholesterol levels were slightly higher in the SED mice at baseline (P < 0.01) but did not differ between EX and SED at final testing.


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  		Table 1. Body weights and plasma lipid levels

 
Gallstone development.   At death, the gallbladder was removed and the gallstones from all mice in each group were pooled and weighed. The pooled weight of the gallstones was 2.5-fold greater in the SED mice than in the EX mice (Fig. 1A). Representative samples of gallbladders from a SED and EX mice are shown in Fig. 1B.


Figure 1
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  		Fig. 1. Pooled gallstone weights (A) and representative gallbladders (B–D) from sedentary (SED) and exercise-trained (EX) mice. Gallstones from all animals in each group (n = 25/group) were pooled and weighed at death. B: intact gallbladder from a mouse in the SED group. C: gallbladder from the same SED mouse with gallstones removed for display. D: intact gallbladder from a mouse in the EX group. Note that the gallbladder in this picture is translucent, and no stones are apparent.

 
Gene expression.   The hepatic expression of selected genes related to liver and bile cholesterol metabolism is shown in Fig. 2A. There was no difference in hepatic mRNA levels for HMGCS, ABCB4, ABCB11, or ABCG5 between the SED and EX mice. However, there was a significant increase in the hepatic expression of LDLr (2.5-fold, P = 0.03), SRB1 (1.7-fold, P = 0.04), and Cyp27 (2.3-fold, P = 0.002) in the EX mice relative to SED, and a trend for an increase in the expression of ABCG8 (1.8-fold, P = 0.1) and HMGCR (1.9-fold, P = 0.1).


Figure 2
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  		Fig. 2. Quantitative RT-qPCR of liver (A) and intestine (B) RNA from SED and EX mice. Total RNA was isolated from the liver, duodenum, and jejunum of 10 mice in each group at death. Two micrograms of RNA was reverse-transcribed into cDNA, which was used for PCR analysis. Cyclophilin was used as the normalizer gene in each tissue. Each value represents the mRNA levels relative to the amount of transcript in the SED mice, which was arbitrarily set to 1.0. LDLr, low-density lipoprotein receptor; SRB1, scavenger receptor class B type 1; HMGCR, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A reductase; HMGCS, HMG-coenzyme A synthase; CYP27, sterol 27 hydroxylase; ABCG5, ABCG8, ABCB11, and ABCB4, ATP binding cassette transporter G5, G8, B11, and B4, respectively; NPC1L1, Niemann-Pick C1-Like 1. Data are expressed as means ± SD. *P ≤ 0.05.

 
The expression of selected genes involved in cholesterol absorption in the intestine is shown in Fig. 2B. In the duodenum, NPC1L1, ABCG5, and ABCG8 mRNA levels were each reduced by 55–65% (P < 0.05 for each) in the EX group compared with SED; however, there were no group differences in the expression of these genes in the ileum.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The major finding of this study is that 12 wk of endurance exercise training attenuated gallstone development in a gallstone-susceptible (C57L/J) strain of mice. To our knowledge, this is the first longitudinal study to demonstrate that exercise training reduces gallstones in any model system.

To examine potential mechanisms for the antilithogenic effects of exercise training seen in this study, we also measured the hepatic and intestinal expression of selected genes involved in cholesterol metabolism that may impact gallstone development. Cholesterol gallstones may develop due to excessive secretion of cholesterol into the bile; if the ratio of biliary cholesterol to bile acids and phospholipids exceeds critical limits, the cholesterol may precipitate and form stones (5). A number of factors may contribute to biliary cholesterol supersaturation, including increases in cholesterol uptake from the circulation, increased cholesterol biosynthesis in the liver, or reduced catabolism of cholesterol to bile acids (23). Changes in the hepatic expression of genes that regulate these factors could significantly affect gallstone formation. Of particular interest, we found a significant increase in the hepatic expression the LDLr, SRB1, and Cyp27. The LDLr is responsible for clearing ApoB-containing lipoproteins (LDL and very-low-density lipoprotein) from the circulation, while SRB1 promotes selective uptake of HDL-cholesterol into the liver (9). Although increases in the expression of these genes may be expected to increase cholesterol secretion into the bile, the expression of Cyp27 was also elevated in the EX mice. Cyp27 is a rate-limiting enzyme in the conversion of cholesterol to bile acids by the "alternative" pathway (26), so increases in this enzyme may help prevent gallstone formation by increasing the bile acid: bile cholesterol ratio. Taken together, these differences in hepatic gene expression between the EX and SED mice indicate a potential mechanism by which exercise training simultaneously improves cholesterol clearance from the circulation while also inhibiting gallstone formation.

Of note, bile acids are normally synthesized from cholesterol primarily through the "classic" pathway initiated by the enzyme Cyp7a1 (26). However, Cyp7a1 is downregulated by cholic acid feeding in C57L/J mice (21), so expression levels in our animals were too low for a robust analysis. A previous pilot study in our lab in C57BL6 mice found a 4.5-fold increase in Cyp7a1 gene expression after 4 wk of voluntary wheel running (Wilund, unpublished observations), but additional studies are needed to confirm this finding.

Exercise did not induce significant changes in mRNA expression of HMGCR, HMGCS, ABCB4, ABCB11, ABCG5, or ABCG8. HMGCR and HMGCS are the rate-limiting enzymes in the de novo synthesis of cholesterol in the liver (10). ABCB4 and ABCB11 promote phospholipid (31) and bile acid (28) secretion, respectively, into bile, while ABCG5 and ABCG8 form a functional dimer that secretes cholesterol into the bile (3). Thus our data suggest that the reduction in gallstones in the EX mice was not due to reductions in hepatic cholesterol synthesis or secretion into the bile, or increases in biliary phospholipid or bile acid secretion.

High cholesterol absorption efficiency in the intestine also can enhance gallstone formation (33), so we measured the intestinal expression of three genes, NPC1L1, ABCG5, and ABCG8, that play a critical role in regulating cholesterol absorption in the duodenum and jejunum, the primary sites of cholesterol absorption (12). NPC1L1 promotes cholesterol absorption by transporting cholesterol from the intestinal lumen into enterocytes (1), while ABCG5 and G8 inhibit cholesterol absorption by effluxing cholesterol from enterocytes back into the intestinal lumen. The expression of each of these genes in the duodenum was reduced by ~60% in the EX mice compared with SED mice. While a reduction in NPC1L1 levels should reduce cholesterol absorption, the concomitant reduction in ABCG5 and G8 expression would be expected to enhance cholesterol absorption, so the overall effects of these changes in gene expression are uncertain. However, one potential explanation is that ABCG5 and ABCG8 expression may have decreased in response to the reduction in NPC1L1, meaning that that if less cholesterol is being transported into enterocytes by NPC1L1, this may reduce ABCG5 and G8 expression as there will be less cholesterol to efflux back into the intestinal lumen. Direct measurements of cholesterol uptake and absorption will be needed to confirm this hypothesis.

There are several limitations to our study. First, because of the small size and weight of gallstones from individual animals, we chose to pool the gallstones from all animals in each group. While this limited our statistical analysis, we felt this was the most accurate way to represent the differences in gallstone weight between the groups. Previous studies have used a variety of methods to estimate gallstone size and weight in mice, but we felt the measurement error using these techniques was too large for a robust analysis. Also, because the SED mice gained significantly more weight than the EX mice, we cannot ensure that the observed changes are due to exercise alone, or due in whole or in part to the reduced weight gain in the EX mice. However, studies in overweight mice indicate that obesity may not be a risk factor for cholesterol gallstone formation in these animals (4), so we do not believe that the differences in weight gain between the EX and SED mice had a significant effect on gallstone development in this study. Finally, to examine potential mechanisms for the antilithogenic effects of the exercise training, we relied on an analysis of mRNA expression in the liver and intestine. Direct measurements of cholesterol absorption and synthesis, biliary lipids, bile secretion, and flow rates are among the measurements needed to specifically address these mechanisms.

In conclusion, we have shown that 12 wk of endurance exercise training attenuates gallstone development in mice. The mechanism for this may lie in changes in expression of several genes related to cholesterol metabolism and bile acid formation. Our exercise training protocol of 45 min of running per day, 5 days/wk, translates to use in a human population. As gallstone disease represents a significant public health problem in the United States and around the world, future studies should investigate the impact of endurance exercise training in preventing gallstone development in susceptible human populations.


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This research was supported by a pilot grant from the University of Illinois Campus Research Board.


   FOOTNOTES
 

Address for reprint requests and other correspondence: K. R. Wilund, Univ. of Illinois, Dept. of Kinesiology and Community Health, 906 S. Goodwin Ave., Urbana, IL 61801 (e-mail: kwilund{at}uiuc.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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  1. Altmann SW, Davis HR Jr, Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 303: 1201–1204, 2004.[Abstract/Free Full Text]
  2. Basso L, McCollum PT, Darling MR, Tocchi A, Tanner WA. A descriptive study of pregnant women with gallstones. Relation to dietary and social habits, education, physical activity, height, and weight. Eur J Epidemiol 8: 629–633, 1992.[CrossRef][Web of Science][Medline]
  3. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290: 1771–1775, 2000.[Abstract/Free Full Text]
  4. Bouchard G, Johnson D, Carver T, Paigen B, Carey MC. Cholesterol gallstone formation in overweight mice establishes that obesity per se is not linked directly to cholelithiasis risk. J Lipid Res 43: 1105–1113, 2002.[Abstract/Free Full Text]
  5. Carey MC, Lamont JT. Cholesterol gallstone formation. 1. Physical-chemistry of bile and biliary lipid secretion. Prog Liver Dis 10: 139–163, 1992.[Medline]
  6. Chuang CZ, Martin LF, LeGardeur BY, Lopez A. Physical activity, biliary lipids, and gallstones in obese subjects. Am J Gastroenterol 96: 1860–1865, 2001.[CrossRef][Web of Science][Medline]
  7. Cuevas A, Miquel JF, Reyes MS, Zanlungo S, Nervi F. Diet as a risk factor for cholesterol gallstone disease. J Am Coll Nutr 23: 187–196, 2004.[Abstract/Free Full Text]
  8. Everhart JE, Khare M, Hill M, Maurer KR. Prevalence and ethnic differences in gallbladder disease in the United States. Gastroenterology 117: 632–639, 1999.[CrossRef][Web of Science][Medline]
  9. Fuchs M, Ivandic B, Muller O, Schalla C, Scheibner J, Bartsch P, Stange EF. Biliary cholesterol hypersecretion in gallstone-susceptible mice is associated with hepatic up-regulation of the high-density lipoprotein receptor SRBI. Hepatology 33: 1451–1459, 2001.[CrossRef][Web of Science][Medline]
  10. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature 343: 425–430, 1990.[CrossRef][Medline]
  11. Gollnick PD, Simmons SW. Physical activity and liver cholesterol. Int Z Angew Physiol 23: 322–330, 1967.[Medline]
  12. Grundy SM. Absorption and metabolism of dietary cholesterol. Annu Rev Nutr 3: 71–96, 1983.[CrossRef][Web of Science][Medline]
  13. Hillebrandt S, Matern S, Lammert F. Mouse models for genetic dissection of polygenic gastrointestinal diseases. Eur J Clin Invest 33: 155–160, 2003.[CrossRef][Web of Science][Medline]
  14. Jorgensen T. Gall stones in a Danish population. Relation to weight, physical activity, smoking, coffee consumption, and diabetes mellitus. Gut 30: 528–534, 1989.[Abstract/Free Full Text]
  15. Khanuja B, Cheah YC, Hunt M, Nishina PM, Wang DQ, Chen HW, Billheimer JT, Carey MC, Paigen B. Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc Natl Acad Sci USA 92: 7729–7733, 1995.[Abstract/Free Full Text]
  16. Kriska AM, Brach JS, Jarvis BJ, Everhart JE, Fabio A, Richardson CR, Howard BV. Physical activity and gallbladder disease determined by ultrasonography. Med Sci Sports Exerc 39: 1927–1932, 2007.
  17. Leitzmann MF, Giovannucci EL, Rimm EB, Stampfer MJ, Spiegelman D, Wing AL, Willett WC. The relation of physical activity to risk for symptomatic gallstone disease in men. Ann Intern Med 128: 417–425, 1998.[Abstract/Free Full Text]
  18. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2–{Delta}{Delta}CT method. Methods 25: 402–408, 2001.[CrossRef][Web of Science][Medline]
  19. Lutton C. Anatomical heterogeneity of the intestinal mucosa and cholesterol homeostasis. A review of studies with normal and genetically hypercholesterolemic (RICO). Rat Digestion 57: 1–10, 1996.
  20. Misciagna G, Centonze S, Leoci C, Guerra V, Cisternino AM, Ceo R, Trevisan M. Diet, physical activity, and gallstones—a population-based, case-control study in southern Italy. Am J Clin Nutr 69: 120–126, 1999.[Abstract/Free Full Text]
  21. Murphy C, Parini P, Wang J, Bjorkhem I, Eggertsen G, Gafvels M. Cholic acid as key regulator of cholesterol synthesis, intestinal absorption and hepatic storage in mice. Biochim Biophys Acta 1735: 167–175, 2005.[Medline]
  22. Paigen B, Morrow A, Brandon C, Mitchell D, Holmes P. Variation in susceptibility to atherosclerosis among inbred strains of mice. Atherosclerosis 57: 65–73, 1985.[CrossRef][Web of Science][Medline]
  23. Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet 368: 230–239, 2006.[CrossRef][Medline]
  24. Sandler RS, Everhart JE, Donowitz M, Adams E, Cronin K, Goodman C, Gemmen E, Shah S, Avdic A, Rubin R. The burden of selected digestive diseases in the United States. Gastroenterology 122: 1500–1511, 2002.[CrossRef][Web of Science][Medline]
  25. Schefer V, Talan MI. Oxygen consumption in adult and AGED C57BL/6J mice during acute treadmill exercise of different intensity. Exp Gerontol 31: 387–392, 1996.[CrossRef][Web of Science][Medline]
  26. Schwarz M, Russell DW, Dietschy JM, Turley SD. Alternate pathways of bile acid synthesis in the cholesterol 7alpha-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding. J Lipid Res 42: 1594–1603, 2001.[Abstract/Free Full Text]
  27. Simko V, Ondreicka R, Chorvathova V, Bobek P. Effect of long-term physical exercise on bile sterols, fecal fat and fatty acid metabolism in rats. J Nutr 100: 1331–1339, 1970.[Abstract/Free Full Text]
  28. Stieger B, Meier Y, Meier PJ. The bile salt export pump. Pflügers Arch 453: 611–620, 2007.[CrossRef][Web of Science][Medline]
  29. Utter A, Goss F. Exercise and gall bladder function. Sports Med 23: 218–227, 1997.[CrossRef][Web of Science][Medline]
  30. Utter AC, Whitcomb DC, Nieman DC, Butterworth DE, Vermillion SS. Effects of exercise training on gallbladder function in an obese female population. Med Sci Sports Exerc 32: 41–45, 2000.
  31. vanBerge-Henegouwen GP, Venneman NG, Portincasa P, Kosters A, van Erpecum KJ, Groen AK. Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease. Scand J Gastroenterol Suppl: 60–69, 2004.
  32. Wang DQ, Paigen B, Carey MC. Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile. J Lipid Res 38: 1395–1411, 1997.[Abstract]
  33. Wang DQ, Zhang L, Wang HH. High cholesterol absorption efficiency and rapid biliary secretion of chylomicron remnant cholesterol enhance cholelithogenesis in gallstone-susceptible mice. Biochim Biophys Acta 1733: 90–99, 2005.[Medline]
  34. Yiamouyiannis CA, Martin BJ, Watkins JB, 3rd. Chronic physical activity alters hepatobiliary excretory function in rats. J Pharmacol Exp Ther 265: 321–327, 1993.[Abstract/Free Full Text]




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