Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-30T23:42:35.789Z Has data issue: false hasContentIssue false
  • English
  • Français

Functional and association studies on the pig HMGCR gene, a cholesterol-synthesis limiting enzyme

Published online by Cambridge University Press:  23 October 2009

A. Cánovas ,
R. Quintanilla ,
D. Gallardo ,
I. Díaz ,
J. L. Noguera ,
O. Ramírez  and
R. N. Pena
A. Cánovas
Affiliation:
IRTA, Genètica i Millora Animal, 191 Alcalde Rovira Roure, 25198 Lleida, Spain
R. Quintanilla
Affiliation:
IRTA, Genètica i Millora Animal, 191 Alcalde Rovira Roure, 25198 Lleida, Spain
D. Gallardo
Affiliation:
Departament de Ciència Animal i dels Aliments, Facultat de Veterinària, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
I. Díaz
Affiliation:
IRTA, Tecnologia dels Aliments, Finca Camps i Armet, 17121 Monells, Spain
J. L. Noguera
Affiliation:
IRTA, Genètica i Millora Animal, 191 Alcalde Rovira Roure, 25198 Lleida, Spain
O. Ramírez
Affiliation:
Departament de Ciència Animal i dels Aliments, Facultat de Veterinària, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
R. N. Pena*
Affiliation:
IRTA, Genètica i Millora Animal, 191 Alcalde Rovira Roure, 25198 Lleida, Spain
*
†E-mail: [email protected]
Get access

Abstract

The 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the rate-limiting enzyme in the biosynthesis of cholesterol. We have studied the role of the HMGCR gene in pig lipid metabolism by means of expression and structural analysis. We describe here the complete coding region of this gene in pigs and report two synonymous single nucleotide polymorphisms in the coding region. We have, additionally, studied the association of one of these polymorphisms (HMGCR:c.807A>C) with several lipid deposition- and cholesterol-related traits in a half-sib population generated from a commercial Duroc line, showing in some families a positive relationship of HMGCR:c.807A allele with serum low-density lipoprotein (LDL)-bound cholesterol and triglyceride levels, and also with intramuscular fat (IMF) content of gluteus medius muscle. We have also assessed the expression levels in muscle and in liver from 68 Duroc individuals corresponding to the most extreme animals for the analysed traits. Liver HMGCR expression correlated negatively with the serum high-density lipoprotein (HDL) levels, carcass lean percentage and stearic acid content, while muscle expression correlated also negatively with the carcass lean percentage, stearic and linoleic acids content, but showed a positive correlation with the serum lipid cholesterol (HDL, LDL and total cholesterol), IMF and muscle oleic and palmitic fatty acid content. With this information, we have performed an association analysis of expression data with lipid metabolism phenotypic levels and the HMGCR genotype. The results indicate that HMGCR expression levels in muscle are different in the two groups of pigs with extreme values for fat deposition and total cholesterol levels, and also between animals with the different HMGCR genotypes.

Keywords

meat quality, fatty acid, intramuscular fat, gene expression, porcine
Type
Full Paper
Information
animal , Volume 4 , Issue 2 , February 2010 , pp. 224 - 233
Copyright
Copyright © The Animal Consortium 2009

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Burkhardt, R, Kenny, EE, Lowe, JK, Birkeland, A, Josowitz, R, Noel, M, Salit, J, Maller, JB, Pe’er, I, Daly, MJ, Altshuler, D, Stoffel, M, Friedman, JM, Breslow, JL 2008. Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13. Arteriosclerosis, Thrombosis and Vascular Biology 28, 2078–2084.Google Scholar
Cayuela, JM, Garrido, MD, Banon, SJ, Ros, JM 2003. Simultaneous HPLC analysis of alpha-tocopherol and cholesterol in fresh pig meat. Journal of Agriculture and Food Chemistry 51, 1120–1124.Google Scholar
Chan, J, Donalson, LM, Kushwaha, RS, Ferdinandusse, S, VandeBerg, JF, VandeBerg, JL 2008. Differential expression of hepatic genes involved in cholesterol homeostasis in high- and low-responding strains of laboratory opossums. Metabolism 57, 718–724.Google Scholar
Chasman, DI, Posada, D, Subrahmanyan, L, Cook, NR, Stanton, VP Jr, Ridker, PM 2004. Pharmacogenetic study of statin therapy and cholesterol reduction. The Journal of the American Medical Association 291, 2821–2827.Google Scholar
Chenna, R, Sugawara, H, Koike, T, Lopez, R, Gibson, TJ, Higgins, DG, Thompson, JD 2003. Multiple sequence alignment with the Clustal series of programs. Nucleic Acids Research 31, 3497–3500.CrossRefGoogle ScholarPubMed
Chomczynski, P, Sacchi, N 1987. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Annals on Biochemistry 162, 156–159.Google Scholar
Datta, S, Wang, L, Moore, DD, Osborne, TF 2006. Regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase promoter by nuclear receptors liver receptor homologue-1 and small heterodimer partner: a mechanism for differential regulation of cholesterol synthesis and uptake. Journal of Biology and Chemistry 281, 807–812.Google Scholar
Davis, AM, White, BA, Wheeler, MB 1995. Rapid communication: a DraI restriction fragment length polymorphism at the porcine 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCoAR) locus. Journal of Animal Science 73, 310.CrossRefGoogle Scholar
Davoli, R, Braglia, S 2007. Molecular approaches in pig breeding to improve meat quality. Brief Functional Genomic Proteomic 6, 313–321.Google Scholar
Fernandez, ML, McNamara, DJ 1991. Regulation of cholesterol and lipoprotein metabolism in guinea pigs mediated by dietary fat quality and quantity. Journal of Nutrition 121, 934–943.Google Scholar
Friesen, JA, Rodwell, VW 2004. The 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductases. Genome Biology 5, 248.1–248.7.Google Scholar
Gallardo, D, Pena, RN, Amills, M, Varona, L, Ramirez, O, Reixach, J, Diaz, I, Tibau, J, Soler, J, Prat-Cuffi, JM, Noguera, JL, Quintanilla, R 2008. Mapping of quantitative trait loci for cholesterol, LDL, HDL, and triglyceride serum concentrations in pigs. Physiological Genomics 35, 199–209.CrossRefGoogle ScholarPubMed
Kajinami, K, Takekoshi, N, Brousseau, ME, Schaefer, EJ 2004. Pharmacogenetics of HMG-CoA reductase inhibitors: exploring the potential for genotype-based individualization of coronary heart disease management. Atherosclerosis 177, 219–234.Google Scholar
Mach, N, Devant, M, Diaz, I, Font-Furnols, M, Oliver, MA, Garcia, JA, Bach, A 2006. Increasing the amount of n-3 fatty acid in meat from young Holstein bulls through nutrition. Journal of Animal Science 84, 3039–3048.Google Scholar
McWhinney, VJ, Pond, WG, Mersmann, HJ 1996. Ontogeny and dietary modulation of 3-hydroxy-3-methylglutaryl-CoA reductase activities in neonatal pigs. Journal of Animal Science 74, 2203–2210.Google Scholar
Medina, MW, Gao, F, Ruan, W, Rotter, JI, Krauss, RM 2008. Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase is associated with plasma low-density lipoprotein cholesterol response to simvastatin. Circulation 118, 355–362.Google Scholar
Nagao, K, Yanagita, T 2008. Bioactive lipids in metabolic syndrome. Progress in Lipid Research 47, 127–146.CrossRefGoogle ScholarPubMed
Ness, GC, Chambers, CM 2000. Feedback and hormonal regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase: the concept of cholesterol buffering capacity. Procedings of the Society of Experimental Biology in Medicine 224, 8–19.Google Scholar
Ohashi, K, Osuga, J, Tozawa, R, Kitamine, T, Yagyu, H, Sekiya, M, Tomita, S, Okazaki, H, Tamura, Y, Yahagi, N, Iizuka, Y, Harada, K, Gotoda, T, Shimano, H, Yamada, N, Ishibashi, S 2003. Early embryonic lethality caused by targeted disruption of the 3-hydroxy-3-methylglutaryl-CoA reductase gene. Journal of Biology and Chemistry 278, 42936–42941.CrossRefGoogle ScholarPubMed
Olsson, V, Pickova, J 2005. The influence of production systems on meat quality, with emphasis on pork. Ambio 34, 338–343.Google Scholar
Osborne, AR, Pollock, VV, Lagor, WR, Ness, GC 2004. Identification of insulin-responsive regions in the HMG-CoA reductase promoter. Biochemistry and Biophysics Research Communications 318, 814–818.Google Scholar
Pinhu, L, Park, JE, Yao, W, Griffiths, MJ 2008. Reference gene selection for real-time polymerase chain reaction in human lung cells subjected to cyclic mechanical strain. Respirology 13, 990–999.Google Scholar
Plastow, GS, Carrión, D, Gil, M, GarcIa-Regueiro, JA, i Furnols, MF, Gispert, M, Oliver, MA, Velarde, A, Guàrdia, MD, Hortós, M, Rius, MA, Sárraga, C, Diaz, I, Valero, A, Sosnicki, A, Klont, R, Dornan, S, Wilkinson, JM, Evans, G, Sargent, C, Davey, G, Connolly, D, Houeix, B, Maltin, CM, Hayes, HE, Anandavijayan, V, Foury, A, Geverink, N, Cairns, M, Tilley, RE, Mormède, P, Blott, SC 2005. Quality pork genes and meat production. Meat Science 70, 409–421.Google Scholar
Pond, WG, Mersmann, HJ 1996. Genetically diverse pig models in nutrition research related to lipoprotein and cholesterol metabolism. In Advances in Swine in Biomedical Research (ed. ME Tumbleson and LB Schook), pp. 843–861. Plenum Press, New York.Google Scholar
Sambrook, J, Russell, D 2001. Molecular Cloning: A Laboratory Manual Cold Spring Harbor. Laboratory Press, Cold Spring Harbor, New York.Google Scholar
Schmitz, G, Langmann, T 2006. Pharmacogenomics of cholesterol-lowering therapy. Vascular Pharmacology 44, 75–89.CrossRefGoogle ScholarPubMed
Schoknecht, PA, Ebner, S, Pond, WG, Zhang, S, McWhinney, V, Wong, WW, Klein, PD, Dudley, M, Goddard-Finegold, J, Mersmann, HJ 1994. Dietary cholesterol supplementation improves growth and behavioral response of pigs selected for genetically high and low serum cholesterol. Journal of Nutrition 124, 305–314.Google Scholar
Telford, DE, Edwards, JY, Lipson, SM, Sutherland, B, Barrett, PH, Burnett, JR, Krul, ES, Keller, BT, Huff, MW 2003. Inhibition of both the apical sodium-dependent bile acid transporter and HMG-CoA reductase markedly enhances the clearance of LDL apoB. Journal of Lipid Research 44, 943–952.Google Scholar
Tong, Y, Zhang, S, Li, H, Su, Z, Kong, X, Liu, H, Xiao, C, Sun, Y, Shi, JJ 2004. 8302A/C and (TTA)n polymorphisms in the HMG-CoA reductase gene may be associated with some plasma lipid metabolic phenotypes in patients with coronary heart disease. Lipids 39, 239–241.CrossRefGoogle ScholarPubMed
van der Steen, HAM, Prall, GFW, Plastow, GS 2005. Application of genomics to the pork industry. Journal of Animal Science 83, E1–E8.Google Scholar
Wilding, JP 2007. The importance of free fatty acids in the development of Type 2 diabetes. Diabetes and Medecine 24, 934–945.Google Scholar
Yuan, JS, Reed, A, Chen, F, Stewart, CN Jr 2006. Statistical analysis of real-time PCR data. BMC Bioinformatics 7(85), 1–12.CrossRefGoogle Scholar