2008 Annual Report
Specific aim 2: We made substantial progress in our experiments with HL-60 cells; however, because of technical difficulties and critical vacancy, we were unable to fully meet the milestone for this specific aim. Instead of continuing this project, we redirected our research effort to determine the effects of plant and marine omega-3 fatty acids on insulin resistance (IR) and nonalcoholic fatty liver disease (NAFLD). Our earlier publications have shown that conjugated linoleic acid (CLA) induced both these metabolic conditions in mice. In a study conducted with mice last year we found that flaxseed oil which is rich in alpha linolenic acid (ALA) completely prevented the CLA-induced IR and partly prevented the NAFLD. These findings were presented at the 2008 ISSFAL meeting and a manuscript is in press in the British Journal of Nutrition. Thus, the milestones for the revised specific aim were fully met. The goals of this research are consistent with the goals of National Program 107 and address Component 5, Health Promoting Properties of Plant and Animal Foods.
Specific aim 3: We have substantially met our milestones for this sub-objective. We determined which downstream signaling pathways derived from TLR activation are modulated by fatty acids, and in turn which target genes are differentially modulated. Identification of the differentially regulated genes and consequent cellular responses will eventually lead us to understand why types of dietary fatty acids differentially affect the risk of development of chronic diseases. Microarray data are currently being analyzed in collaboration with Dr. Kevin Dawson. We have investigated the mechanism by which fatty acids differentially modulate TLR4 activation. The results showed that saturated fatty acid, lauric acid stimulated TLR4 dimerization and the recruitment of TLR4 to lipid raft fractions, whereas, n-3 PUFA docosahexaenoic (DHA) inhibited the dimerization and recruitment. The goals of this research are consistent with the goals of National Program 107 and address Component 5, Health Promoting Properties of Plant and Animal Foods.
According to a 2002 survey, 35% of the US adults have insulin resistance (IR) which leads to the development of type 2 diabetes. ARS scientists in the Immunity and Disease Prevention Research Unit in Davis, CA believe the major reason for this increase in IR is the high intake of trans fatty acids and inadequate intake of omega-3 fatty acids. To test this hypothesis a study was conducted in mice where the diet was supplemented either with 0.5% CLA (a trans fatty acid found in processed vegetable oils) or CLA along with 0.5% flaxseed oil (0.3% alpha linolenic acid). The CLA containing diets caused a 7 fold increase in the concentration of circulating insulin, which was restored to the normal levels by the concomitant feeding of flaxseed oil. If CLA and flaxseed oil have similar effects in human beings, then these findings may have enormous implications for the prevention of diabetes. This addresses NP 107, Component 5.2. Nuclear factor-kappa B (NFkB) inhibition due to plant polyphenols. Certain anti-inflammatory plant polyphenols (e.g.,resveratrol, curcumin) are known to inhibit NFkB transcription factor. However, the direct molecular targets of these polyphenols are not identified. Since NFkB is a common downstream signaling molecule of Toll-like receptors (TLRs), ARS scientists in the Immunity and Disease Prevention Research Unit in Davis, CA determined whether these polyphenols inhibit TLR signaling pathways. The results showed that curcumin inhibits the activation of TLR4 by interfering the dimerization of TLR4 which is the initial step of receptor activation, whereas resveratrol inhibits the downstream kinase enzyme of TLR4 signaling pathways. These results suggest that signaling molecules in TLR signaling pathways may be attractive targets for dietary preventive strategy for many inflammatory chronic diseases. This relates to NP 107, Component 5.
5.Significant Activities that Support Special Target Populations
Results from the DHA and CLA studies discussed above improve the health of obese subjects and those with abnormal blood lipids.
Youn, H., Lim, H., Lee, H., Hwang, D.H., Yang, M., Jeon, R., Ryu, J. 2008. Garlic (Allium sativum) Extracts Inhibits Lipopolysaccharide-Induced Toll-Like Receptor 4 Dimerization. Bioscience Biotechnology and Biochemistry 72(2):368-375, 2008.
Youn, H.S., Lee, J.K., Choi, Y.J., Saitoh, S.I., Miyake, K., Hwang, D.H., Lee, J.Y. 2008. Cinnamaldehyde suppresses Toll-like receptor 4 activation mediated through the inhibition of receptor oligomerization. 2007. Biochemical Pharmacology. Vol.75(2), p.494-502, 2008.
Zhao, L., Lee, J.Y., Hwang, D.H. The Phosphatidylinositol 3-Kinase/Akt Pathway Negatively Regulates Nod2-Mediated NF-kB Pathway. 2008. Biochemical Pharmacology. 75:1515-1525, 2008.
Lee, J., Lee, J., Lee, M., Hwang, D.H., Youn, H. 2007. Acrolein with an alpha, beta-unsaturated Carbonyl Group Inhibits LPS-induced Homodimerization of Toll-like Receptor 4. Molecules and Cells. Vol.25, No2, 253-257.
Kelley, D.S., Siegel, D., Vemuri, M., Chung, G.H., Mackey, B.E. 2007. Docosahexaenoic acid supplementation decreases remnant-like particle-cholesterol and improves omega-3 index in hypertriglyceridemic men1-3.. Journal of Nutrition. 2007. Journal Nutrition 138:30-35, 2008.
Vermuri, M., Kelley, D.S., Erickson, K. 2008. Health Effects of Foods Rich in Polyphenols. Book Chapter, "Wild-Type Food in Health Promotion and Disease Prevention, The Columbus Concept. De Meester, Fabien; Watson, Ronald R. (Eds.) Humana Press, Chapter 27;pp.393-412.
Vemuri, M., Kelley, D.S. 2007. The Effects of Dietary Fatty Acids on Lipid Metabolism. Book Chapter in, "Fatty Acids in Foods and their Health Implications, third edition". CRC Press Taylor & Francis Group pp.591-630.