Performing Department
Ag Nutrition and Vet Sciences
Non Technical Summary
The impact of cardiovascular disease represents one of the greatest challenges confronting the modern healthcare system. Within the wide ranging spectrum of cardiovascular disorders there is a complexity that makes it a formidable challenge to both public and private healthcare organizations around the world. The estimated toll in human life and economic cost, combined with the inestimable effect on the quality of life for individuals and their families, transcends all gender, racial, ethnic and socio-economic groups. In the United States alone it is estimated that around 71 million people suffer some form of cardiovascular disorder. Within the State of Nevada heart disease and stroke accounted for 5,649 deaths in 2004, corresponding to 32% of all deaths in the State. That same year the estimated financial cost to the State with respect to diseases of the circulatory system was a staggering $3,085,109,650 (Department of Health and Human Services, 2006). We are currently in the midst of an ever-increasing obesity epidemic. Currently, Nevada has the 32nd highest rate of adult obesity in the nation at 25.1% and the 11th highest rate of overweight youths (ages 10-17) at 34.2% (Trust for America's Health and the Robert Wood Johnson Foundation, 2010). In Washoe County it is estimated that 21% of the population are obese, while this value is slightly higher in Carson City, where it is estimated to be 24% (Nevada Public Health Foundation, 2010). Diet and nutrition can have a direct and profound effect on the risk factors related to heart disease and stroke, both from a detrimental and a beneficial perspective. For example, eating diets high in saturated fats, triglycerides, and cholesterol increases the development of atherosclerosis. In addition, improper nutrition can also lead to excessive weight gain and obesity. On the other hand, dietary intervention can have a positive impact on the risk factors for heart disease and current key recommendations for addressing obesity in Nevada include ensuring that every adult and child has access to coverage for preventative medical services, including nutrition and obesity counseling, and screening for obesity-related diseases. This project aims to extend previous studies undertaken by the PI assessing the ability of a grape seed extract that is rich in procyanidins to lower serum triglyceride levels (Del Bas et al. 2008, Del Bas et al. 2009) by providing further insight into its' molecular mode of action. This extract is marketed as a health product that can be incorporated into dietary supplements or functional foods. Consequently, since the extract can potentially aid in the eradication of factors associated with heart disease, such as high serum triglyceride levels, its use as a nutritional supplement to aid in lowering the prevalence of CVD is of particular relevance to the citizens of the State of Nevada.
Animal Health Component
(N/A)
Research Effort Categories
Basic
100%
Applied
(N/A)
Developmental
(N/A)
Goals / Objectives
1) Consumption of food-borne bioactive compoundscanprotect against human disease such as cancer, inflammation, birth defects and microbial infection. We will determine the mechanisms by which selected compounds exert their protective action. 3) Selected classes of bioactive compounds show potential for beneficial or adverse effects on human health. We will discover bioactive compounds that have beneficial or adverse effects on human health.
The overall objective of this proposal is to understand, at the molecular level, how a grape seed procyanidin extract (GSPE) lowers serum triglyceride levels. The proposed project aims to answer the following three main questions: 1. How does GSPE enhance the transactivation of bile acid bound FXR 2. Does the level of bile acids in vivo affect the ability of GSPE to lower serum triglyceride levels 3. Which component or components in the grape seed procyanidin extract is/are responsible for the enhanced activity of bile acid bound FXR The rationale for the proposed research is based on the knowledge that FXR ligands are potential therapeutic targets for treatment of metabolic disorders such as dyslipidemia. Our studies will provide further insight into the actions of FXR as well as those of GSPE and procyanidins both in vitro and in vivo. Outcomes of the proposed research will ultimately provide a mechanism-based agent for the lowering of triglyceride levels and to aid in the development of a natural supplement comprising the most potent component(s) responsible for mediating this effect. We plan to test our hypothesis and accomplish the objective of this application by pursuing the following three specific aims: Aim 1: Define the molecular actions of GSPE with respect to FXR activation. Aim 2: Establish the direct relationship between endogenous levels of bile acids and the actions of GSPE and its' ability to lower serum triglyceride levels in vivo. Aim 3: Identify which procyanidin(s) enhance bile acid bound-FXR transactivation.
Project Methods
Understanding the molecular effects of bioactive dietary constituents in the development of the metabolic syndrome and obesity is an important area of research. Nuclear hormone receptors (NHRs) play important roles in various metabolic pathways and we will study the beneficial effects of bioactive dietary constituents, such as GSPE, on NHRs to further understand their molecular mode of action. Studies will use cell culture models, incorporating transient transfection studies and mammalian two hybrid assays, and in vivo mouse models, which will include a candidate gene approach as well as microarray technology to determine alterations in gene expression.