Different statins produce highly divergent changes in gene expression profiles of human hepatoma cells: a pilot study
Languages of publication
Statins are inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the key enzyme of the sterol biosynthesis pathway. Statin therapy is commonly regarded as well tolerated. However, serious adverse effects have also been reported, especially during high-dose statin therapy. The aim of our study was to investigate the effect of statins on gene expression profiles in human hepatoma HepG2 cells using Affymetrix Human Genome U133 Plus 2.0 arrays. Expression of 102, 857 and 1091 genes was changed substantially in HepG2 cells treated with simvastatin, fluvastatin and atorvastatin, respectively. Pathway and gene ontology analysis showed that many of the genes with changed expression levels were involved in a broad range of metabolic processes. The presented data clearly indicate substantial differences between the tested statins.
- Ahn SC (2008) Neuromuscular complications of statins. Phys Med Rehabil Clin N Am 19: 47-59.
- Bergheanu SC, Reijmers T, Zwinderman AH, Bobeldijk I, Ramaker R, Liem AH, van der Greef J, Hankemeier T, Jukema JW (2008) Lipidomic approach to evaluate rosuvastatin and atorvastatin at various dosages: investigating differential effects among statins. JACC Cardiovasc Interv 1: 192-201.
- Bergheanu SC, Van Tol A, Dallinga-Thie GM, Liem A, Dunselman PH, Van der Bom JG, Jukema JW (2007) Effect of rosuvastatin versus atorvastatin treatment on paraoxonase-1 activity in men with established cardiovascular disease and a low HDL-cholesterol. Curr Med Res Opin 23: 2235-2240.
- Buhaescu I, Izzedine H (2007) Mevalonate pathway: a review of clinical and therapeutical implications. Clin Biochem 40: 575-584.
- Charlton-Menys V, Durrington PN (2007) Human cholesterol metabolism and therapeutic molecules. Exp Physiol 93: 27-42.
- Chopra V, Choksi PU, Cavusoglu E (2007) Beyond lipid lowering: the anti-hypertensive role of statins. Cardiovasc Drugs Ther 21: 161-169.
- Ditschuneit HH, Kuhn K, Ditschuneit H (1991) Comparison of different HMG-CoA reductase inhibitors. Eur J Clin Pharmacol 40 (Suppl 1): S27-S32.
- Furberg CD (1999) Natural statins and stroke risk. Circulation 99: 185-188.
- Gerber R, Ryan JD, Clark DS (2004) Cell-based screen of HMG-CoA reductase inhibitors and expression regulators using LC-MS. Anal Biochem 329: 28-34.
- Hagemenas FC, Illingworth DR (1989) Cholesterol homeostasis in mononuclear leukocytes from patients with familial hypercholesterolemia treated with lovastatin. Arteriosclerosis 9: 355-361.
- Healy D, Morgan R, Chinnaswamy S (2009) Transient global amnesia associated with statin intake. BMJ Case Reports doi:10.1136/bcr.06.2008.0033.
- Heart Protection Study Collaborative Group (2002) MRC/BHF Heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360: 7-22.
- Hodel C (2002) Myopathy and rhabdomyolysis with lipid-lowering drugs. Toxicol Lett 128: 159-168.
- Leszczynska A, Burzynska B, Plochocka D, Kaminska J, Zimnicka M, Kania M, Kiliszek M, Wysocka-Kapcinska M, Danikiewicz W, Szkopinska A (2009) Investigating the effects of statins on cellular lipid metabolism using a yeast expression system. PLoS One 12: e8499.
- Liao JK (2002) Isoprenoids as mediators of the biological effects of statins. J Clin Invest 110: 285-288.
- Maeda A, Yano T, Itoh Y, Kakumori M, Kubota T, Egashira N, Oishi R (2010) Down-regulation of RhoA is involved in the cytotoxic action of lipophilic statins in HepG2 cells. Atherosclerosis 208: 112-118.
- Mangravite LM, Thorn CF, Krauss RM (2006) Clinical implications of pharmacogenomics of statin treatment. Pharmacogenomics J 6: 360-374.
- McCarey DW, McInnes IB, Madhok R, Hampson R, Scherbakov O, Ford I, Capell HA, Sattar N (2004) Trial of atorvastatin in rheumatoid arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 363: 2015-2021.
- Morikawa S, Murakami T, Yamazaki H, Izumi A, Saito Y, Hamakubo T, Kodama T (2005) Analysis of the global RNA expression profiles of skeletal muscle cells treated with statins. J Atheroscler Thromb 12: 121-131.
- Mullen PJ, Lüscher B, Scharnagl H, Krähenbühl S, Brecht K. (2010) Effect of simvastatin on cholesterol metabolism in C2C12 myotubes and HepG2 cells, and consequences for statin-induced myopathy. Biochem Pharmacol 79: 1200-1209.
- Olsson AG, Eriksson M, Johnson O, Kjellström T, Lanke J, Larsen ML, Pedersen T, Tikkanen MJ, Wiklund O (2003) A 52-week, multicenter, randomized, parallel-group, double-blind, double-dummy study to assess the efficacy of atorvastatin and simvastatin in reaching low-density lipoprotein cholesterol and triglyceride targets: the treat-to-target (3T) study. Clin Ther 25: 119-138.
- Pandak WR, Stravitz RT, Lucas V, Heuman DM, Chiang JY (1996) Hep G2 cells: a model for studies on regulation of human cholesterol 7alpha-hydroxylase at the molecular level. Am J Physiol 270: G401-410.
- Pfaffl MW, Horgan GW, Dempfle L (2002) Relative expression software tool (REST) for group-wise comparison and statistical analysis of relative expression results in real-time PCR. Nucleic Acids Res 30: e36.
- Prosser LA, Stinnett AA, Goldman PA, Williams LW, Hunink MG, Goldman L, Weinstein MC (2000) Cost-effectiveness of cholesterol-lowering therapies according to selected patient characteristics. Ann Intern Med 132: 769-779.
- Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J, ASCOT investigators (2003) Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 361: 1149-1158.
- Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, Ford I, Gaw A, Hyland M, Jukema JW, Kamper AM, Macfarlane PW, Meinders AE, Norrie J, Packard CJ, Perry IJ, Stott DJ, Sweeney BJ, Twomey C, Westendorp RG, PROSPER study group (2002) Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 360: 1623-1630.
- Van Greevenbroek MM, Vermeulen VM, de Bruin TW (2002) Familial combined hyperlipidemia plasma stimulates protein secretion by HepG2 cells: identification of fibronectin in the differential secretion proteome. J Lipid Res 43: 1846-1854.
- Wierzbicki AS, Lumb PJ, Semra Y, Chik G, Christ ER, Crook MA (1999) Atorvastatin compared with simvastatin-based therapies in the management of severe familial hyperlipidaemias. QJM 92: 387-394.
- Yu JG, Sewright K, Hubal MJ, Liu JX, Schwartz LM, Hoffman EP, Clarkson PM (2009) Investigation of gene expression in C(2)C(12) myotubes following simvastatin application and mechanical strain. J Atheroscler Thromb 16: 21-29.
Publication order reference