Lunastatin™ Research
Cholesterol-Lowering Property of a Chromatin-Binding Peptide Derived from Soy
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.
Lunastatin (a.k.a. lunasin) is a recently discovered bioactive soy component with a novel chromatin binding property. Synthetic lunastatin has been shown to significantly reduce the acetylation of histone H3 by PCAF (p300/CBP-associated factor). Transcriptional regulation of HMG-CoA reductase (HMG) and LDL receptor (LDL-R) by Sterol Regulatory Element-Binding Proteins (SREBP) in cholesterol-free media requires the selective recruitment of different co-regulatory factors, CREB/CBP for HMG and SP1 for LDL-R. 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 and by inhibiting acetylation, lunastatin may reduce its expression.
Cell culture of HepG2 liver cells shows that synthetic lunastatin can indeed significantly reduce HMG expression by 50% in cholesterol-free media. In contrast, LDL-R 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 expression by lunastatin lowers intracellular cholesterol levels that keeps SREBP activated, contributing to the upregulation of LDL-R expression. Initial results from RT-PCR experiments show the corresponding decrease of HMG and the increase of LDL-R mRNA levels in lunastatin-treated, cholesterol-free media, which will be further validated by real-time quantitative RT-PCR. Hence, these studies show that lunastatin has the potential to reduce cholesterol levels by directly inhibiting gene expression of HMG, whose enzymatic activity is suppressed by cholesterol-lowering statin drugs, and by increasing LDL-R expression, which enhances clearance of plasma LDL cholesterol.
[publication in progress]
