Research

ALFREDO F. GALVEZ ^{1, 2, *,} FU CHUNJIANG², JIM PORTER²,
MONTY KERLEY²

1 SOY LABS, LLC, FAIRFIELD, CA; PROJECT SCIENTIST, CENTER OF EXCELLENCE FOR NUTRITIONAL GENOMICS, UNIVERSITY OF CALIFORNIA AT DAVIS

2 DEPARTMENT OF ANIMAL SCIENCE, UNIVERSITY OF MISSOURI, COLUMBIA, MO * CORRESPONDING AUTHOR

ABSTRACT

The American Heart Association recently reported that soy protein lowers LDL cholesterol by only 3%, contrary to the FDA health claim on soy protein. We now report the discovery of a chromatin-binding peptide from soy that could very well be the active factor responsible for the LDL cholesterol-lowering effect attributed to soy proteins and help clarify clinical results summarized in the recent AHA report.

Lunasin is a recently discovered bioactive soy component with a novel chromatin binding property. Lunasin has been shown to significantly reduce the acetylation of histone H3 by the histone acetylase enzyme, PCAF (p300/CBP-associated factor) but not by p300 or HAT1. Transcriptional regulation of HMG CoA reductase and LDL receptor genes by Sterol Regulatory Element Binding Proteins (SREBP) in cholesterol-free media requires the selective recruitment of different co-regulatory factors, CREB/CBP for HMG-CoA reductase and SP1 for LDL receptor. CREB-binding protein (CBP) interacts with the activation domain of SREBP and has been shown to associate with PCAF to specifically acetylate histone H3. The acetylation of histone H3 by PCAF is required for SREBP-controlled transcriptional activation of HMG-CoA reductase and by inhibiting H3 acetylation, lunasin can potentially reduce its expression.

Cell culture of HepG2 liver cells shows that treatment with lunasin can indeed significantly reduce HMG-CoA reductase expression by 50% in cholesterol-free media. In contrast, LDL receptor expression has increased by 60%, which can be explained in part by the coordinate increase in expression of its co-transcriptional activator, Sp1. Also, the inhibition of HMG-CoA reductase expression by lunasin lowers intracellular cholesterol levels that keeps SREBP activated, contributing to the upregulation of LDL receptor expression. Results from RT-PCR experiments show the corresponding reduction of HMG-CoA reductase and the increase of LDL receptor mRNA transcript levels in lunasin-treated, cholesterol-free media, which has also been validated by real-time quantitative RT-PCR. Hence, these studies show that lunasin has the potential to reduce LDL and total cholesterol levels by directly inhibiting gene expression of HMG-CoA reductase, which reduces cholesterol biosynthesis, and by increasing LDL receptor expression, which enhances clearance of plasma LDL cholesterol. The presence of the lunasin peptide in soy protein preparations provides a plausible mechanism of action to explain the cholesterol-lowering effect attributed to soy protein and paves the way for optimizing soy protein ingredients to maximize its heart-healthy benefits.