Abstract 10693: Identification of Lunasin as the Active Component in Soy Protein Responsible for Reducing LDL Cholesterol and Risk of Cardiovascular Disease

Abstract

Soy protein has an approved FDA health claim for reducing LDL cholesterol and CVD risk but the active component and mechanism of action are unknown. We tested the hypothesis that the lunasin peptide is the active component in soy protein responsible for lowering LDL cholesterol. The lunasin soy peptide binds specifically to histone H3 and inhibits H3-Lysine 14 acetylation by PCAF histone acetylase enzyme. Transcriptional activation of HMG Co-A reductase, the rate-limiting enzyme for cholesterol biosynthesis requires the specific acetylation of histone H3 by PCAF. By inhibiting PCAF acetylation of H3-Lysine 14, lunasin was show to significantly reduce HMG Co-A reductase expression in HepG2 liver cells grown in cholesterol-free media. Westerns and RT-PCR experiments also revealed that the presence of lunasin increases LDL receptor expression, which can be attributed to the coordinate increase in expression of SP1 co-transcriptional activator. These results provide lunasin with a mechanism for lowering LDL cholesterol levels by directly inhibiting gene expression of HMG Co-A reductase to lower cholesterol biosynthesis and by increasing LDL receptor levels to enhance clearance of plasma LDL cholesterol. Using a lunasin bioactivity assay, we were able to produce a lunasin-enriched soy extract (LSE) containing 100-200 fold more bioactive lunasin than soy protein isolates. To test the in vivo efficacy of LSE, we conducted a food supplementation experiment on five pigs that have high LDL cholesterol due to mutations in their LDL receptor genes. The pigs were fed casein-based diets and after two weeks their casein diet was supplemented with 250 mg LSE everyday for eight weeks. Blood draws and lipid panel testing were done at -2w (before casein diet), 0w (2 weeks casein), 4w (4w casein + 250 mg LES) and 8w (8w casein + 250 mg LES). Results showed that casein diet increased LDL cholesterol levels in the LDL-R mutant pigs by an average of 6.7%. The addition of 250 mg of LES in casein diet reduced LDL cholesterol by 8.6% and and 6.4% after 4 and 8 weeks of treatment, respectively. These results prove that lunasin is the active nutrient in soy protein responsible for LDL cholesterol lowering and its mechanism of action is by reducing cholesterol biosynthesis in the liver.