The metabolic syndrome has emerged as a constellation of risk factors that markedly increase the risk of diabetes and cardiovascular disease. The metabolic syndrome consists of central obesity, atherogenic dyslipidemia, elevations of blood pressure and plasma glucose, and prothrombotic and pro-inflammatory states. It increases the risk for cardiovascular disease by 2-fold and raises the risk for type 2 diabetes by approximately 5-fold. As the prevalence of obesity and diabetes is rising at an alarming rate, the incidence of this morbid syndrome is expected to continue to grow both in the United States and worldwide, and thus, there is a greater need for the development of new safe and effective combinations of drugs, more efficacious drugs as well as multifunctional drugs that can be used as valuable clinical tools in the management of individual components of this syndrome. Previous studies from this laboratory have shown that the desert plant, Larrea tridentata (Creosote Bush) derived nordihydroguaiaretic Acid (NDGA), a potent lipoxygenase (LO) inhibitor, has profound effects on multiple components of the metabolic syndrome including lowering of blood glucose, free fatty acids (FFA) and triglyceride levels, attenuation of elevated blood pressure and improvement in insulin sensitivity in several rodent models of insulin resistance, type 2 diabetes, dyslipidemia and hypertension. The overall goal of this project is to elucidate the molecular mechanism by which NDGA exerts its hypolipidemic action in the liver. The central hypothesis is that NDGA exerts its hypolipidemic actions by altering the activity of key lipid-sensitive nuclear transcription factors, which, in turn, improve hepatic lipid metabolism, particularly through an inhibition of hepatic lipogenesis and increased channeling of fatty acids toward oxidation, all of which severely curtail the supply of fatty acids needed for triglyceride (TG) synthesis, TG storage and VLDL-TG production/ secretion. Additionally, NDGA may also directly impact VLDL-TG production, assembly and secretion. To test these hypotheses three specific aims are proposed.
Aim 1 will characterize the effects of NDGA on molecular, biochemical and metabolic events associated with hepatic fatty acid uptake and oxidation in animal and cell models of hyperlipidemia.
Aim 2 will determine the mechanism of inhibitory action of NDGA on hepatic de novo lipogenesis (DNL).
Aim 3 will evaluate the effects of NDGA on hepatic VLDL-TG production, assembly and secretion. A greater understanding of the molecular mechanism(s) by which NDGA exerts its hypolipidemic action is likely to provide important clues which eventually may lead to the development of NDGA (or its derivative(s)) as a new, effective therapeutic agent in the management of dyslipidemia and possibly other central components of the metabolic syndrome.

Public Health Relevance

Metabolic syndrome has emerged as a constellation of risk factors that markedly increase the risk of type 2 diabetes and cardiovascular disease (CVD). Because the prevalence of diabetes and obesity is rising at an alarming rate, the incidence of this morbid syndrome is expected to continue to grow both in the United States and worldwide, and thus, there is a greater need for the development of new safe and effective combinations of drugs, more efficacious drugs as well as multifunctional drugs that can be used as valuable clinical tools in the management of this syndrome. The goal of this project is to elucidate the molecular mechanism by which NDGA lowers elevated blood lipids by improving the lipid metabolism in the liver. A greater understanding of the molecular mechanism(s) by which NDGA exerts its hypolipidemic action is likely to provide important clues which eventually may lead to the development of NDGA (or some form of its derivative) as a new, effective therapeutic agent in the management of dyslipidemia and possibly other central components of the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092473-05
Application #
8423055
Study Section
Special Emphasis Panel (ZRG1-DIG-C (04))
Program Officer
Hasan, Ahmed AK
Project Start
2009-02-15
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$337,408
Indirect Cost
$101,788
Name
Palo Alto Institute for Research & Edu, Inc.
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
Zaidi, Syed Kashif; Shen, Wen-Jun; Bittner, Stefanie et al. (2014) p38 MAPK regulates steroidogenesis through transcriptional repression of STAR gene. J Mol Endocrinol 53:1-16
Zhang, Haiyan; Shen, Wen-Jun; Cortez, Yuan et al. (2013) Nordihydroguaiaretic acid improves metabolic dysregulation and aberrant hepatic lipid metabolism in mice by both PPAR*-dependent and -independent pathways. Am J Physiol Gastrointest Liver Physiol 304:G72-86
Ueno, Masami; Shen, Wen-Jun; Patel, Shailja et al. (2013) Fat-specific protein 27 modulates nuclear factor of activated T cells 5 and the cellular response to stress. J Lipid Res 54:734-43
Bielicki, John K; Zhang, Haiyan; Cortez, Yuan et al. (2010) A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice. J Lipid Res 51:1496-503
Yue, Pin; Chen, Zhouji; Nassir, Fatiha et al. (2010) Enhanced hepatic apoA-I secretion and peripheral efflux of cholesterol and phospholipid in CD36 null mice. PLoS One 5:e9906
Azhar, Salman (2010) Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease. Future Cardiol 6:657-91