The effect of exercise training on upregulation of molecular markers of bile acid metabolism in the liver of ovariectomized rats fed a cholesterol-rich diet

Farahnak, Zahra; Tomaz, Luciane Magri; Bergeron, Raynald; Chapados, Natalie; Lavoie, Jean-Marc

The effect of exercise training on upregulation of molecular markers of bile acid metabolism in the liver of ovariectomized rats fed a cholesterol-rich diet

Document Type : Original Article(s)

Authors

Zahra Farahnak ¹

Luciane Magri Tomaz ²

Raynald Bergeron ³

Natalie Chapados ⁴

Jean-Marc Lavoie ⁵

¹ Department of Kinesiologie, University of Montreal, Montreal, Canada

² Laboratory of Exercise Physiology, Department of Physiological Sciences, Federal University of Sao Carlos, Sao Carlos, Brazil

³ Associate Professor, Department of Kinesiologie, University of Montreal, Montreal, Canada

⁴ Assistant Professor, Institute of Research of Hospital Montfort, Institute of Savoir of Montfort AND School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada

⁵ Professor, Department of Kinesiologie, University of Montreal, Montreal, Canada

Abstract

BACKGROUND: Small heterodimer partner (SHP) is an important transcriptional factor involved in the regulation of glucose, lipid, and bile acid metabolism in the liver. SHP has been reported to be down-regulated in ovariectomized (Ovx) mice and up-regulated by estrogens suggesting a link between estrogens and SHP. The aim of the present study was to determine the effects of exercise training on SHP and key molecular markers of cholesterol and bile acid homeostasis in Ovx rats under cholesterol feeding. METHODS: Our main experimental group was composed of Ovx rats fed a high-cholesterol diet (Ovx-Chol) that was compared to a group of Ovx rats fed a standard diet (Ovx-SD) and a group of sham operated rats fed the cholesterol diet (Sham-Chol). These three groups of Ovx and sham rats were subdivided into either voluntary wheel running (Tr) or sedentary (Sed) groups for 5 weeks. The mRNA expression of all genes was measured by quantitative real-time polymerase chain reaction. RESULTS: Liver total cholesterol levels were not affected by exercise training in any of the experimental conditions. Cholesterol feeding in both sham and Ovx rats resulted in significantly higher hepatic cholesterol accumulation than in Ovx-SD (P < 0.001). Hepatic low-density lipoprotein-receptor (LDL-R) involved in cholesterol uptake from circulation was not influenced by training. A main effect of training was, however, found for transcripts of SHP and cholesterol 7 alpha-hydroxylase (CYP7A1, P < 0.05). CYP7A1 is the main gene involved in bile acid biosynthesis from cholesterol. CONCLUSION: These results suggest that voluntary wheel running modulates cholesterol metabolism in Ovx animals through up-regulation of SHP and bile acid formation.

Keywords

Exercise

Cholesterol 7 Alpha-Hydroxylase

Rat, Cholesterol

Low Density Lipoprotein Receptor

Chaudhuri A, Borade NG, Hazra SK. A study of heart rate variablity tests and lipid profile in postmenopausal women. J Indian Med Assoc 2012; 110(4): 228, 230-28, 232.
Kaur A, Jindal S, Kaur IP, Chopra K. Effect of sesamol on the pathophysiological changes induced by surgical menopause in rodents. Climacteric 2013; 16(4): 426-37.
Ngo Sock ET, Cote I, Mentor JS, Prud'homme D, Bergeron R, Lavoie JM. Ovariectomy stimulates hepatic fat and cholesterol accumulation in high-fat diet-fed rats. Horm Metab Res 2013; 45(4): 283-90.
Ngo Sock ET, Chapados NA, Lavoie JM. LDL receptor and Pcsk9 transcripts are decreased in liver of ovariectomized rats: Effects of exercise training. Horm Metab Res 2014; 46(8): 550-5.
Cote I, Ngo Sock ET, Levy E, Lavoie JM. An atherogenic diet decreases liver FXR gene expression and causes severe hepatic steatosis and hepatic cholesterol accumulation: Effect of endurance training. Eur J Nutr 2013; 52(5): 1523-32.
Savard C, Tartaglione EV, Kuver R, Haigh WG, Farrell GC, Subramanian S, et al. Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis. Hepatology 2013; 57(1): 81-92.
Cote I, Chapados NA, Lavoie JM. Impaired VLDL assembly: A novel mechanism contributing to hepatic lipid accumulation following ovariectomy and high-fat/high-cholesterol diets? Br J Nutr 2014; 112(10): 1592-600.
Farahnak Z, Cote I, Ngo Sock ET, Lavoie JM. High dietary cholesterol and ovariectomy in rats repress gene expression of key markers of VLDL and bile acid metabolism in liver. Lipids Health Dis 2015; 14: 125.
Meissner M, Lombardo E, Havinga R, Tietge UJ, Kuipers F, Groen AK. Voluntary wheel running increases bile acid as well as cholesterol excretion and decreases atherosclerosis in hypercholesterolemic mice. Atherosclerosis 2011; 218(2): 323-9.
Lee YS, Chanda D, Sim J, Park YY, Choi HS. Structure and function of the atypical orphan nuclear receptor small heterodimer partner. Int Rev Cytol 2007; 261: 117-58.
Zhang Y, Hagedorn CH, Wang L. Role of nuclear receptor SHP in metabolism and cancer. Biochim Biophys Acta 2011; 1812(8): 893-908.
Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, et al. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 2000; 6(3): 517-26.
Wang H, Chen J, Hollister K, Sowers LC, Forman BM. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 1999; 3(5): 543-53.
Lee YK, Moore DD. Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner. J Biol Chem 2002; 277(4): 2463-7.
Jelinek DF, Andersson S, Slaughter CA, Russell DW. Cloning and regulation of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis. J Biol Chem 1990; 265(14): 8190-7.
Wang X, Lu Y, Wang E, Zhang Z, Xiong X, Zhang H, et al. Hepatic estrogen receptor alpha improves hepatosteatosis through upregulation of small heterodimer partner. J Hepatol 2015; 63(1): 183-90.
Robertson MC, Owens RE, Klindt J, Friesen HG. Ovariectomy leads to a rapid increase in rat placental lactogen secretion. Endocrinology 1984; 114(5): 1805-11.
Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem 1957; 226(1): 497-509.
Durstine JL, Grandjean PW, Cox CA, Thompson PD. Lipids, lipoproteins, and exercise. J Cardiopulm Rehabil 2002; 22(6): 385-98.
Halverstadt A, Phares DA, Wilund KR, Goldberg AP, Hagberg JM. Endurance exercise training raises high-density lipoprotein cholesterol and lowers small low-density lipoprotein and very low-density lipoprotein independent of body fat phenotypes in older men and women. Metabolism 2007; 56(4): 444-50.
Meissner M, Nijstad N, Kuipers F, Tietge UJ. Voluntary exercise increases cholesterol efflux but not macrophage reverse cholesterol transport in vivo in mice. Nutr Metab (Lond) 2010; 7: 54.
Nishigori H, Tomura H, Tonooka N, Kanamori M, Yamada S, Sho K, et al. Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc Natl Acad Sci U S A 2001; 98(2): 575-80.
Hung CC, Farooqi IS, Ong K, Luan J, Keogh JM, Pembrey M, et al. Contribution of variants in the small heterodimer partner gene to birthweight, adiposity, and insulin levels: Mutational analysis and association studies in multiple populations. Diabetes 2003; 52(5): 1288-91.
Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, et al. Bile acids: Natural ligands for an orphan nuclear receptor. Science 1999; 284(5418): 1365-8.
Wilund KR, Feeney LA, Tomayko EJ, Chung HR, Kim K. Endurance exercise training reduces gallstone development in mice. J Appl Physiol (1985) 2008; 104(3): 761-5.
Pinto PR, Rocco DD, Okuda LS, Machado-Lima A, Castilho G, da Silva KS, et al. Aerobic exercise training enhances the in vivo cholesterol trafficking from macrophages to the liver independently of changes in the expression of genes involved in lipid flux in macrophages and aorta. Lipids Health Dis 2015; 14: 109.
Lai K, Harnish DC, Evans MJ. Estrogen receptor alpha regulates expression of the orphan receptor small heterodimer partner. J Biol Chem 2003; 278(38): 36418-29.
Evans MJ, Lai K, Shaw LJ, Harnish DC, Chadwick CC. Estrogen receptor alpha inhibits IL-1beta induction of gene expression in the mouse liver. Endocrinology 2002; 143(7): 2559-70.
Pighon A, Gutkowska J, Jankowski M, Rabasa-Lhoret R, Lavoie JM. Exercise training in ovariectomized rats stimulates estrogenic-like effects on expression of genes involved in lipid accumulation and subclinical inflammation in liver. Metabolism 2011; 60(5): 629-39.
Wen S, Jadhav KS, Williamson DL, Rideout TC. Treadmill exercise training modulates hepatic cholesterol metabolism and circulating PCSK9 concentration in high-fat-fed mice. J Lipids 2013; 2013: 908048.