Horm Metab Res 2014; 46(08): 550-555
DOI: 10.1055/s-0034-1370910
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

LDL Receptor and Pcsk9 Transcripts are Decreased in Liver of Ovariectomized Rats: Effects of Exercise Training

E. T. Ngo Sock
1   Department of Kinesiology, University of Montreal, Montreal, Quebec, Canada
,
N. A. Chapados
2   Nutrition and Metabolism Research Unit Montfort Hospital Research Institute, Ottawa, Ontario, Canada
,
J.-M. Lavoie
1   Department of Kinesiology, University of Montreal, Montreal, Quebec, Canada
› Author Affiliations
Further Information

Publication History

received 25 November 2013

accepted 05 February 2014

Publication Date:
11 March 2014 (online)

Abstract

The aim of this study was to determine the effects of ovariectomy in rats on hepatic gene expression of key molecules involved in cholesterol metabolism and to verify if exercise training may play a role in preventing hypercholesterolemia in Ovx rats. Sprague-Dawley rats were ovariectomized (Ovx) or sham-operated (Sham) and were either trained (Tr) on treadmill or kept sedentary (Sed) for 8 weeks. Rats were divided into 5 groups: Sham-Sed, Sham-Tr, Ovx-Sed, Ovx-Tr and Ovx with 17β-estradiol supplementation (Ovx-E2). Ovx animals had significantly (p<0.05) higher body weight, adiposity, liver total cholesterol (TC) content and hypercholesterolemia compared to Sham rats. In contrast, gene expression of hepatic low-density lipoprotein receptor (LDL-R), LDL receptor-related protein (Lrp1), proprotein convertase subtilisin/kexin type 9 (Pcsk9), sterol regulatory element binding protein 2 (SREBP-2) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCoA-r) were reduced (p<0.05) in Ovx compared to Sham rats. Hepatic mRNA levels of scavenger receptor class B member 1 (SR-B1) and ATP-binding cassette subfamily A member 1 (ABCA1) (hepatic and intestinal) were higher (p<0.05) in Ovx compared to Sham rats. All of these molecular changes were corrected in Ovx-E2. Exercise training, significantly reversed the effect of Ovx on adiposity, plasma triglyceride, TC and mRNA expression of SREBP-2 but had no effect on all other hepatic genes expression. These data indicate that hypercholesterolemia in Ovx rats is associated with a reduction of hepatic LDL-R and Lrp1 gene expression.

Supporting Information

 
  • References

  • 1 Masson DY, van-Charvet L. Raising HDL-cholesterol: the future drug therapy for atherosclerosis?. Med Sci (Paris) 2008; 24: 341-343
  • 2 Matthews KA, Meilahn E, Kuller LH, Kelsey SF, Caggiula AW, Wing RR. Menopause and risk factors for coronary heart disease. N Engl J Med 1989; 321: 641-646
  • 3 Kimura T, Matsumoto T, Akiyoshi M, Owa Y, Miyasaka N, Aso T, Moritani T. Body fat and blood lipids in postmenopausal women are related to resting autonomic nervous system activity. Eur J Appl Physiol 2006; 97: 542-547
  • 4 Kaur A, Jindal S, Kaur IP, Chopra K. Effect of sesamol on the pathophysiological changes induced by surgical menopause in rodents. Climacteric 2013; 16: 426-437
  • 5 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: 230-232
  • 6 Park Y, Kwon HY, Shimi MK, Rhyu MR, Lee Y. Improved lipid profile in ovariectomized rats by red ginseng extract. Pharmazie 2011; 66: 450-453
  • 7 Garber CE, Blissmer B, Deschenes MR, Franklin BA, Lamonte MJ, Lee IM, Nieman DC, Swain DP. American College of Sports Medicine position stand. Quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise. Med Sci Sports Exerc 2011; 43: 1334-1359
  • 8 Oh HY, Lim S, Lee JM, Kim DY, Ann ES, Yoon S. A combination of soy isoflavone supplementation and exercise improves lipid profiles and protects antioxidant defense-systems against exercise-induced oxidative stress in ovariectomized rats. Biofactors 2007; 29: 175-185
  • 9 Zoth N, Weigt C, Zengin S, Selder O, Selke N, Kalicinski M, Piechotta M, Diel P. Metabolic effects of estrogen substitution in combination with targeted exercise training on the therapy of obesity in ovariectomized Wistar rats. J Steroid Biochem Mol Biol 2012; 130: 64-72
  • 10 Bilheimer DW, Goldstein JL, Grundy SM, Starzl TE, Brown MS. Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia. N Engl J Med 1984; 311: 1658-1664
  • 11 Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, Boileau C, Magot T, Krempf M. Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler Thromb Vasc Biol 2004; 24: 1448-1453
  • 12 Niesen M, Bedi M, Lopez D. Diabetes alters LDL receptor and PCSK9 expression in rat liver. Arch Biochem Biophys 2008; 470: 111-115
  • 13 Abifadel M, Varret M, Rabes JP, Allard D, Ouguerram K, Devillers M, Cruaud C, Benjannet S, Wickham L, Erlich D, Derre A, Villeger L, Farnier M, Beucler I, Bruckert E, Chambaz J, Chanu B, Lecerf JM, Luc G, Moulin P, Weissenbach J, Prat A, Krempf M, Junien C, Seidah NG, Boileau C. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34: 154-156
  • 14 Dubuc G, Chamberland A, Wassef H, Davignon J, Seidah NG, Bernier L, Prat A. Statins upregulate PCSK9, the gene encoding the proprotein convertase neural apoptosis-regulated convertase-1 implicated in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 2004; 24: 1454-1459
  • 15 Smith JR, Osborne TF, Goldstein JL, Brown MS. Identification of nucleotides responsible for enhancer activity of sterol regulatory element in low density lipoprotein receptor gene. J Biol Chem 1990; 265: 2306-2310
  • 16 Ge XZ, Tian PF, Lin Q, Huo Q. The influence of soybean isoflavone on expression of low density lipoprotein receptor (LDLR) mRNA in ovariectomied rats. Zhong Yao Cai 2006; 29: 349-351
  • 17 Kato M, Ogawa H, Kishida T, Ebihara K. The mechanism of the cholesterol-lowering effect of water-insoluble fish protein in ovariectomised rats. Br J Nutr 2009; 102: 816-824
  • 18 Persson L, Galman C, Angelin B, Rudling M. Importance of proprotein convertase subtilisin/kexin type 9 in the hormonal and dietary regulation of rat liver low-density lipoprotein receptors. Endocrinology 2009; 150: 1140-1146
  • 19 Rohlmann A, Gotthardt M, Hammer RE, Herz J. Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants. J Clin Invest 1998; 101: 689-695
  • 20 Rader DJ. Molecular regulation of HDL metabolism and function: implications for novel therapies. J Clin Invest 2006; 116: 3090-3100
  • 21 Landschulz KT, Pathak RK, Rigotti A, Krieger M, Hobbs HH. Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat. J Clin Invest 1996; 98: 984-995
  • 22 Ghanbari-Niaki A, Khabazian BM, Hossaini-Kakhak SA, Rahbarizadeh F, Hedayati M. Treadmill exercise enhances ABCA1 expression in rat liver. Biochem Biophys Res Commun 2007; 361: 841-846
  • 23 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
  • 24 Rocco DD, Okuda LS, Pinto RS, Ferreira FD, Kubo SK, Nakandakare ER, Quintao EC, Catanozi S, Passarelli M. Aerobic exercise improves reverse cholesterol transport in cholesteryl ester transfer protein transgenic mice. Lipids 2011; 46: 617-625
  • 25 Robertson MC, Owens RE, Klindt J, Friesen HG. Ovariectomy leads to a rapid increase in rat placental lactogen secretion. Endocrinology 1984; 114: 1805-1811
  • 26 Shinoda M, Latour MG, Lavoie JM. Effects of physical training on body composition and organ weights in ovariectomized and hyperestrogenic rats. Int J Obes Relat Metab Disord 2002; 26: 335-343
  • 27 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: 497-509
  • 28 Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18: 499-502
  • 29 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: 283-290
  • 30 Di Croce L, Bruscalupi G, Trentalance A. Independent behavior of rat liver LDL receptor and HMGCoA reductase under estrogen treatment. Biochem Biophys Res Commun 1996; 224: 345-350
  • 31 Ness GC, Zhao Z, Lopez D. Inhibitors of cholesterol biosynthesis increase hepatic low-density lipoprotein receptor protein degradation. Arch Biochem Biophys 1996; 325: 242-248
  • 32 Rashid S, Curtis DE, Garuti R, Anderson NN, Bashmakov Y, Ho YK, Hammer RE, Moon YA, Horton JD. Decreased plasma cholesterol and hypersensitivity to statins in mice lacking Pcsk9. Proc Natl Acad Sci USA 2005; 102: 5374-5379
  • 33 Costet P, Cariou B, Lambert G, Lalanne F, Lardeux B, Jarnoux AL, Grefhorst A, Staels B, Krempf M. Hepatic PCSK9 expression is regulated by nutritional status via insulin and sterol regulatory element-binding protein 1c. J Biol Chem 2006; 281: 6211-6218
  • 34 Jeong HJ, Lee HS, Kim KS, Kim YK, Yoon D, Park SW. Sterol-dependent regulation of proprotein convertase subtilisin/kexin type 9 expression by sterol-regulatory element binding protein-2. J Lipid Res 2008; 49: 399-409
  • 35 Moon JH, Kim HJ, Kim HM, Yang AH, Lee BW, Kang ES, Lee HC, Cha BS. Upregulation of hepatic LRP1 by rosiglitazone: a possible novel mechanism of the beneficial effect of thiazolidinediones on atherogenic dyslipidemia. J Mol Endocrinol 2012; 49: 165-174
  • 36 Ueda Y, Gong E, Royer L, Cooper PN, Francone OL, Rubin EM. Relationship between expression levels and atherogenesis in scavenger receptor class B, type I transgenics. J Biol Chem 2000; 275: 20368-20373
  • 37 Derby CA, Crawford SL, Pasternak RC, Sowers M, Sternfeld B, Matthews KA. Lipid changes during the menopause transition in relation to age and weight: the Study of Women’s Health Across the Nation. Am J Epidemiol 2009; 169: 1352-1361
  • 38 Barsalani R, Chapados NA, Lavoie JM. Hepatic VLDL-TG production and MTP gene expression are decreased in ovariectomized rats: effects of exercise training. Horm Metab Res 2010; 42: 860-867
  • 39 Hao L, Wang Y, Duan Y, Bu S. Effects of treadmill exercise training on liver fat accumulation and estrogen receptor alpha expression in intact and ovariectomized rats with or without estrogen replacement treatment. Eur J Appl Physiol 2010; 109: 879-886
  • 40 Leaf DA. The effect of physical exercise on reverse cholesterol transport. Metabolism 2003; 52: 950-957