Soy Isoflavones Affect Sterol Regulatory Element Binding Proteins (SREBPs) and SREBP-Regulated Genes in HepG2 Cells

Abstract

Soy intake reduces cholesterol levels. However, both the identity of the soy component or components that contribute to this reduction and the cellular mechanism producing this reduction are unknown. Soy consists of protein, lipids, fiber, and phytochemicals including isoflavones. We propose that the isoflavone component of soy mediates this effect, at least in part, by affecting cellular sterol homeostasis. We investigated the effects of an isoflavone-containing soy extract and the individual isoflavones on the maturation of the sterol regulatory element binding proteins (SREBP) and the expression of SRE-regulated genes controlling lipid metabolism. We found a corresponding increase in the mature form of SREBP-2 in both soy extract- and isoflavone-treated HepG2 cells, whereas there was no significant change in the levels of SREBP-1. 3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase protein and HMG CoA synthase mRNA levels also increased. When HepG2 cells were transiently transfected with HMG CoA synthase and LDL receptor reporter plasmids there was an increase in expression in response to soy extract or isoflavone treatment from both of these promoters, but this induction was blunted in the presence of sterols (P < 0.05). The mechanism responsible for this effect may be via a statin-like inhibition of HMG CoA reductase enzyme activity or by enhanced SREBP processing via the SREBP cleavage activating protein. We hypothesize that maturation of SREBP and induction of SRE-regulated genes produce an increase in surface LDL receptor expression that increases the clearance of plasma cholesterol, thus decreasing plasma cholesterol levels.

Soy protein reduces hepatic lipotoxicity in hyperinsulinemic obese Zucker fa/fa rats

“…Evidence is emerging that dietary phytoestrogens play a beneficial role in decreasing serum lipid levels (36), although our results showed that SREBP-1 in cultured hepatocytes was not regulated by the presence of daidzein and genistein, the main isoflavones in soy. These results are in agreement with those described by Shay and colleagues (37), in which SREBP-1 expression was not affected by isoflavones in HepG2 cells, as well as studies in humans in which the consumption of soy-associated isoflavones was not related to changes in LDL-or HDL-cholesterol (38). However, there is evidence that SREBP-2 is increased in the presence of isoflavones (37).…”

“…These results are in agreement with those described by Shay and colleagues (37), in which SREBP-1 expression was not affected by isoflavones in HepG2 cells, as well as studies in humans in which the consumption of soy-associated isoflavones was not related to changes in LDL-or HDL-cholesterol (38). However, there is evidence that SREBP-2 is increased in the presence of isoflavones (37).…”

Genistein, Resveratrol, and 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside Induce Cytochrome P450 4F2 Expression through an AMP-Activated Protein Kinase-Dependent Pathway

“…Genistein has been reported to activate the transcription of SREBP-regulated genes as well as increase the abundance of the mature, active form of SREBP-2 in nuclei of HepG2 cells (Mullen et al, 2004). SREBP-2 could also be activated because of the inhibitory effects of AMPK activation on cholesterol synthesis.…”

Characterization of the Isoflavone Pratensein as a Novel Transcriptional Up-Regulator of Scavenger Receptor Class B Type I in HepG2 Cells

“…A functional SRE was identified within Ϫ288 bp and Ϫ297 bp, adjacent to an Sp1-binding site. 14) Mullen et al 26) reported that in HepG2 cells, isoflavone-containing soy extract and individual isoflavone increased the mature form of SREBP-2. It is also known that isoflavones may affect other pathway involved in lipid and sterol metabolism.…”