Dietary Isoflavones Reduce Plasma Cholesterol and Atherosclerosis in C57BL/6 Mice but not LDL Receptor-Deficient Mice

Manuscript received 24 October 1997. Initial reviews completed 17 December 1997. Revision accepted 9 February 1998.

Department of Medicine and the Nutritional Sciences Program, University of Washington, Seattle, WA 98195

Susceptibility to atherosclerosis is determined by a combination of genetic and environmental factors, including diet. Consumption of diets rich in soy protein has been claimed to protect against the development of atherosclerosis. Potential mechanisms include cholesterol lowering, inhibition of lipoprotein oxidation and inhibition of cell proliferation by soy proteins or isoflavones, such as genistein, that are present in soy. This study was designed to determine whether soy isoflavones confer protection against atherosclerosis in mice and whether they reduce serum cholesterol levels and lipoprotein oxidation. C57BL/6 and LDL receptor-deficient (LDLr-null) mice were fed soy protein-based, high fat diets with isoflavones present (IF+, 20.85 g/100 g protein, 0.027 g/100 g genistein, 0.009 g/100 g daidzein) or diets from which isoflavones, and possibly other components, had been extracted (IF, 20.0 g/100 g protein, 0.002 g/100 g genistein, 0.001 g/100 g daidzein). Because LDLr-null mice develop extensive atherosclerosis and hypercholesterolemia after minimal time on a high fat diet, they were fed the diets for 6 wk, whereas C57BL/6 mice were fed the diets for 10 wk. Plasma cholesterol levels did not differ between LDLr-null mice fed IF and those fed IF+, but were 30% lower in C57BL/6 mice fed the IF+ diet than in those fed the IF diet. Susceptibility of LDL to oxidative modification, measured as the lag phase of conjugated diene formation in LDLr-null mice, was not altered by isoflavone consumption. All LDLr-null mice developed atherosclerosis, and the presence or deficiency of dietary isoflavones did not influence atherosclerotic lesion area. In contrast, atherosclerotic lesion area was significantly reduced in C57BL/6 mice fed IF+ compared with those fed IF. Thus, this study demonstrates that although the isoflavone-containing diet resulted in a reduction in cholesterol levels in C57BL/6 mice, it had no effect on cholesterol levels or on susceptibility of LDL to oxidative modification in LDLr-null mice. Further, dietary isoflavones did not protect against the development of atherosclerosis in LDLr-null mice but did decrease atherosclerosis in C57BL/6 mice. These findings suggest that soy isoflavones might lower cholesterol levels by increasing LDL receptor activity, and the reduction in cholesterol may offer some protection against atherosclerosis.

The Journal of Nutrition Vol. 128 No. 6 June 1998, pp. 954-959
Copyright ©1998 by the American Society for Nutritional Sciences

This article has been cited by other articles:

				B. L. Lindshield, J. L. King, A. Wyss, R. Goralczyk, C.-H. Lu, N. A. Ford, and J. W. Erdman Jr Lycopene Biodistribution Is Altered in 15,15'-Carotenoid Monooxygenase Knockout Mice J. Nutr., December 1, 2008; 138(12): 2367 - 2371. [Abstract] [Full Text] [PDF]

				A. Orgaard and L. Jensen The Effects of Soy Isoflavones on Obesity Experimental Biology and Medicine, September 1, 2008; 233(9): 1066 - 1080. [Abstract] [Full Text] [PDF]

				L. Al-Nakkash, L. L. Clarke, G. E. Rottinghaus, Y. J. Chen, K. Cooper, and L. J. Rubin Dietary Genistein Stimulates Anion Secretion Across Female Murine Intestine J. Nutr., November 1, 2006; 136(11): 2785 - 2790. [Abstract] [Full Text] [PDF]

				B. L McVeigh, B. L Dillingham, J. W Lampe, and A. M Duncan Effect of soy protein varying in isoflavone content on serum lipids in healthy young men Am. J. Clinical Nutrition, February 1, 2006; 83(2): 244 - 251. [Abstract] [Full Text] [PDF]

				I. Sethy-Coraci, L. W. Crock, and S. C. Silverstein PAF-receptor antagonists, lovastatin, and the PTK inhibitor genistein inhibit H2O2 secretion by macrophages cultured on oxidized-LDL matrices J. Leukoc. Biol., November 1, 2005; 78(5): 1166 - 1174. [Abstract] [Full Text] [PDF]

				S. Zhan and S. C Ho Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile Am. J. Clinical Nutrition, February 1, 2005; 81(2): 397 - 408. [Abstract] [Full Text] [PDF]

				R. Vidal, S. Hernandez-Vallejo, T. Pauquai, O. Texier, M. Rousset, J. Chambaz, S. Demignot, and J.-M. Lacorte Apple procyanidins decrease cholesterol esterification and lipoprotein secretion in Caco-2/TC7 enterocytes J. Lipid Res., February 1, 2005; 46(2): 258 - 268. [Abstract] [Full Text] [PDF]

				E. Mullen, R. M. Brown, T. F. Osborne, and N. F. Shay Soy Isoflavones Affect Sterol Regulatory Element Binding Proteins (SREBPs) and SREBP-Regulated Genes in HepG2 Cells J. Nutr., November 1, 2004; 134(11): 2942 - 2947. [Abstract] [Full Text] [PDF]

				Y. Lin, G. W. Meijer, M. A. Vermeer, and E. A. Trautwein Soy Protein Enhances the Cholesterol-Lowering Effect of Plant Sterol Esters in Cholesterol-Fed Hamsters J. Nutr., January 1, 2004; 134(1): 143 - 148. [Abstract] [Full Text] [PDF]

				J. D. Wagner, D. C. Schwenke, K. A. Greaves, L. Zhang, M. S. Anthony, R. M. Blair, M. K. Shadoan, and J. K. Williams Soy Protein With Isoflavones, but not an Isoflavone-Rich Supplement, Improves Arterial Low-Density Lipoprotein Metabolism and Atherogenesis Arterioscler. Thromb. Vasc. Biol., December 1, 2003; 23(12): 2241 - 2246. [Abstract] [Full Text] [PDF]

				T. Song, S.-O. Lee, P. A. Murphy, and S. Hendrich Soy Protein With or Without Isoflavones, Soy Germ and Soy Germ Extract, and Daidzein Lessen Plasma Cholesterol Levels in Golden Syrian Hamsters Experimental Biology and Medicine, October 1, 2003; 228(9): 1063 - 1068. [Abstract] [Full Text] [PDF]

				S. J. Bhathena, A. A. Ali, C. Haudenschild, P. Latham, T. Ranich, A. I. Mohamed, C. T. Hansen, and M. T. Velasquez Dietary Flaxseed Meal is More Protective Than Soy Protein Concentrate Against Hypertriglyceridemia and Steatosis of the Liver in an Animal Model of Obesity J. Am. Coll. Nutr., April 1, 2003; 22(2): 157 - 164. [Abstract] [Full Text] [PDF]

				M. Xia, W. H. Ling, J. Ma, D. D. Kitts, and J. Zawistowski Supplementation of Diets with the Black Rice Pigment Fraction Attenuates Atherosclerotic Plaque Formation in Apolipoprotein E Deficient Mice J. Nutr., March 1, 2003; 133(3): 744 - 751. [Abstract] [Full Text] [PDF]

				R. M. Blair, S. E. Appt, C. Bennetau-Pelissero, T. B. Clarkson, M. S. Anthony, V. Lamothe, and S. M. Potter Dietary Soy and Soy Isoflavones Have Gender-Specific Effects on Plasma Lipids and Isoflavones in Golden Syrian F1B Hybrid Hamsters J. Nutr., December 1, 2002; 132(12): 3585 - 3591. [Abstract] [Full Text] [PDF]

				M. S. Anthony Phytoestrogens and Cardiovascular Disease: Where's the Meat? Arterioscler. Thromb. Vasc. Biol., August 1, 2002; 22(8): 1245 - 1247. [Full Text] [PDF]

				M. R. Adams, D. L. Golden, M. S. Anthony, T. C. Register, and J. K. Williams The Inhibitory Effect of Soy Protein Isolate on Atherosclerosis in Mice Does Not Require the Presence of LDL Receptors or Alteration of Plasma Lipoproteins J. Nutr., January 1, 2002; 132(1): 43 - 49. [Abstract] [Full Text] [PDF]

				E. A. Lucas, D. A. Khalil, B. P. Daggy, and B. H. Arjmandi Ethanol-Extracted Soy Protein Isolate Does Not Modulate Serum Cholesterol in Golden Syrian Hamsters: A Model of Postmenopausal Hypercholesterolemia J. Nutr., February 1, 2001; 131(2): 211 - 214. [Abstract] [Full Text]

				J. Yamakoshi, M. K. Piskula, T. Izumi, K. Tobe, M. Saito, S. Kataoka, A. Obata, and M. Kikuchi Isoflavone Aglycone-Rich Extract without Soy Protein Attenuates Atherosclerosis Development in Cholesterol-Fed Rabbits J. Nutr., August 1, 2000; 130(8): 1887 - 1893. [Abstract] [Full Text]

				B. E Merz-Demlow, A. M Duncan, K. E Wangen, X. Xu, T. P Carr, W. R Phipps, and M. S Kurzer Soy isoflavones improve plasma lipids in normocholesterolemic, premenopausal women Am. J. Clinical Nutrition, June 1, 2000; 71(6): 1462 - 1469. [Abstract] [Full Text] [PDF]

				E. A. Kirk, M. C. Dinauer, H. Rosen, A. Chait, J. W. Heinecke, and R. C. LeBoeuf Impaired Superoxide Production Due to a Deficiency in Phagocyte NADPH Oxidase Fails to Inhibit Atherosclerosis in Mice Arterioscler. Thromb. Vasc. Biol., June 1, 2000; 20(6): 1529 - 1535. [Abstract] [Full Text] [PDF]

				L. Wroblewski Lissin and J. P. Cooke Phytoestrogens and cardiovascular health J. Am. Coll. Cardiol., May 1, 2000; 35(6): 1403 - 1410. [Abstract] [Full Text] [PDF]

				D. R. Finco and T. L. Cooper Soy Protein Increases Glomerular Filtration Rate in Dogs with Normal or Reduced Renal Function J. Nutr., April 1, 2000; 130(4): 745 - 748. [Abstract] [Full Text]

				K. A. Greaves, J. S. Parks, J. K. Williams, and J. D. Wagner Intact Dietary Soy Protein, but Not Adding an Isoflavone-Rich Soy Extract to Casein, Improves Plasma Lipids in Ovariectomized Cynomolgus Monkeys J. Nutr., August 1, 1999; 129(8): 1585 - 1592. [Abstract] [Full Text]

				K. D. R. Setchell and A. Cassidy Dietary Isoflavones: Biological Effects and Relevance to Human Health J. Nutr., March 1, 1999; 129(3): 758 - 758. [Abstract] [Full Text]

				M. J. Evans, A. Eckert, K. Lai, S. J. Adelman, and D. C. Harnish Reciprocal Antagonism Between Estrogen Receptor and NF-{kappa}B Activity In Vivo Circ. Res., October 26, 2001; 89(9): 823 - 830. [Abstract] [Full Text] [PDF]