The Effect of Soy Isoflavones on Cellular Sterol Regulation

Soy consumption is known to reduce serum cholesterol levels, thereby decreasing the risk of cardiovascular disease. However, the physiological mechanisms and the components of soy that are responsible for this effect are not known. It is our hypothesis that the hypocholesterolemic effects of soy are mediated at least in part by isoflavone-mediated regulation of the Sterol Regulatory Element Binding Proteins (SREBPs) and the Sterol Regulatory Element- (SRE) regulated genes. In HepG2 cells exposed to isoflavones, an increase in the mature form of SREBP-2 and a corresponding increase in the expression of the SRE-regulated genes HMGCR, HMG CoA synthase and the LDL receptor was observed. The observed isoflavone-mediated increase was found to be blunted by the presence of cholesterol. To see if similar results could be observed in vivo, we carried out a 10 day soy feeding study in C57BL/6J mice. Male mice fed isoflavone-containing soy exhibited enhanced decreases in serum lipid levels compared to female mice. While there was a slight increase in hepatic SREBP-2 protein levels in isoflavone fed mice, there was no effect on SRE-regulated gene expression. We then investigated the mechanism by which the isoflavones upregulated SREBP and SRE-regulated genes in vitro. In vitro, genistein acted as a proteasome inhibitor but daidzein did not. Genistein also increased phosphorylation of HMGCR, a modification associated with reduced enzymatic action. Daidzein did not increase phosphorylation of HMGCR in preliminary studies. In conclustion, isoflavones may be increasing SREBP and SRE-regulated genes in vitro but they do not appear to have the same effect in vivo. Most likely, there are multiple mechanisms by which the increase is caused; genistein and daidzein may act by different mechanisms.