Central Objective of Center:

The central objective of the Center for Botanical Lipids at Wake Forest University School of Medicine is to test and determine the mechanistic basis of action, the safety, and the efficacy for fatty acid-based dietary supplements for the prevention and treatment of chronic human diseases associated with inflammation.

Lipid mediators of inflammation and disease. An important mediator of inflammation and human disease is arachidonic acid (AA), a polyunsaturated fatty acid derived from our diets (Figure 1) that is found in the membranes of all cells, including those of the immune system.



Stimulated during inflammation, arachidonic acid can be transformed into inflammatory messengers known as prostaglandins and leukotrienes, which can be key drivers of inflammation (see Figure 2). Free arachidonic acid may be metabolized by 5-lipoxygenase (5-LO) to leukotrienes, or by one of the two types of enzymes known as cyclooxygenase, (COX I or COX II) to form prostaglandins and thromboxanes.



Leukotrienes, prostaglandins and thromboxanes have been implicated in diverse physiological processes, including asthma, inflammation, carcinogenesis, hemostasis, parturition, maintenance of renal function, pain and fever. Given of the central importance of this pathway to health and disease, over $10 billion per year is spent by consumers to block various inflammatory mediators in the pathway and their resulting effects on signs and symptoms of disease. Most inhibitors provide some relief, but side effects may be problematic (aspirin and ibuprofen irritate the stomach, some COX 2 inhibitors appear to have adverse vascular effects). Consequently, there is significant interest in finding other approaches to managing these diseases and symptoms.

Dietary manipulation of inflammatory lipids. Since AA is derived from dietary lipids (see Figure 1) and it is of central importance to human disease, there has also been a large research effort over the last 20 years to determine how production of these important inflammatory substances can be controlled by dietary manipulation. As detailed in Figure 3, dietary linoleic acid is a primary source of n-6 fatty acids in human diets and its conversion to AA is tightly controlled by limiting the -5 and -6 desaturation enzyme steps. All projects in the Center for Botanical Lipids focus on botanical fatty acids in this one specific pathway involving the elongation and desaturation of n-3 and n-6 fatty acids (see Figure 3).



The left side of the figure shows the pathway by which dietary linoleic acid (LA), the initial member of the n-6 family of fatty acids, can be transformed to AA. The right side of the pathway shows how a-linolenic acid, the initial member of the n-3 pathway, is converted to eicosapentaenoic acid (EPA). EPA and another member of the n-3 family, docosahexaenoic acid (DHA) are fatty acids found in high concentrations in marine oils that have been shown to have health benefits. These fatty acids have been demonstrated to inhibit the conversion of AA to several mediators of inflammation. These fatty acids can also be converted to natural receptor antagonists that compete with AA products. Both of these processes are thought to attenuate inflammatory responses in a variety of diseases. Additionally these marine fatty acids have been shown to be highly effective in reducing atherosclerosis and hypertriglyceridemia in a variety of conditions. In spite of the beneficial effects of marine oils, the consumption of n-3 fatty acids in the North American population is low.

The key question that this Center addresses is: Are there botanical fatty acids in the n-6 and n-3 pathways that are effective in blocking recognized biochemical pathways in lipid metabolism, thereby reducing inflammatory and hyperlipidemic responses associated with diseases such as asthma and atherosclerosis?

There are three primary botanicals that are the focus of the four projects in the Center. Flax seed oil (Linum usitatissium) contains -linolenic acid (18:3, n-3), echuim seed oil (Echium Plantagineum) contains stearidonic acid (18:4,n-3) and borage seed oil (Borago officinalis) is rich in gamma linolenic acid (18:3, n-6). Each botanical oil provides a metabolic precursor in the n-3 or n-6 pathways and thus could modify the metabolism of AA by producing EPA and DHA. Figure 3 highlights the points in the n-6 and n-3 pathways where each project focuses on the health benefits of particular botanical seed oil. This attention to one important pathway provides a constant focal point for all projects in the Center. Further details can be found under each project heading.