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Research Newsletter-Spring/Summer 2011

NOT ALL FATS ARE CREATED EQUAL

An interview with Donald B. Jump, Ph.D.
Professor of Nutrition
LPI Principal Investigator


Q. You're from the East Coast, but you spent a few years at Oregon State University in the 1970s. What were you doing here then?

A. I was working with George Beaudreau in the Department of Agricultural Chemistry. I had completed my master's degree at Rutgers and wanted a change. I grew up in Delaware, where the highest point is 400 feet above sea level, and I had seen pictures of the West and thought that would be a great place to go. While doing my master's work, I worked for the Institute of Cancer Research and learned how to culture cells, mainly mammary cancer cells. I worked with George for about three years on cell culture and retroviruses and decided to go back to graduate school for a doctorate in biochemistry from Georgetown University.

Q. You rose through the ranks to become a professor at Michigan State University and then joined the Linus Pauling Institute in 2007. What attracted you to LPI?

A. LPI is an internationally recognized center for nutrition research with a strong focus in the area of micronutrients, antioxidants, and supplements. My area of research is omega-3 fatty acids as regulators of lipid metabolism. Omega-3 fatty acids, also called n-3 fatty acids, are often taken as supplements. N-3 fatty acids are generally beneficial to human health. I was attracted to the LPI because of its capacity to carry out sophisticated analyses of lipids using chromatographic and mass spectrometric methods.

Q. What do you like to do in your free time?

A. My wife and I work on our old house and property. The property was neglected when we purchased it in 2007; we have renovated some parts of the house and made some improvements to the property. We also have a boat and like to sail off South Beach near Newport. We really like the coast. I grew up on the East Coast, and my wife is from Oregon, so we both have an affinity for the ocean.

Q. In the early 1980s, you studied the effect of thyroid hormones on liver function. What did you find?

A. Thyroid hormones are hydrophobic hormones that regulate nuclear receptors; these receptors regulate gene expression. When I was a post-doctoral fellow at the University of Minnesota with Jack Oppenheimer, we established that thyroid hormone receptors are found in or bound to active regions on DNA (chromatin). I learned a lot about endocrinology during my time at the University of Minnesota; that knowledge had a significant influence on my first academic position at Michigan State University (MSU).

Q. Are there interactions between thyroid hormones and dietary factors that affect liver function?

A. There is significant interaction between carbohydrates and thyroid hormone—a synergy in the control of genes involved in lipid metabolism. Glucose, insulin, and thyroid hormones were found to regulate multiple genes involved in liver fat metabolism. At MSU, we had established mechanisms to measure gene expression in the liver; we carried out time-course studies to examine the effects of thyroid hormone action and sucrose (a simple carbohydrate) on liver gene expression. We applied this same approach to examine the effect of dietary fat and carbohydrate on liver gene expression. Rats were fed high-sucrose diets or diets supplemented with n-3 and n-6 fatty acids to examine their effects on liver gene transcription. Sucrose stimulated the expression of genes that make fat, while polyunsaturated fatty acids attenuated the expression of these genes. This discovery was the first to document effects of dietary fatty acids on gene expression, and it set the stage for much of our future research.

Q. Your cell culture studies with fat cells showed that a form of vitamin A called retinoic acid regulates certain genes involved in lipid metabolism. What impact does that have on health?

A. That's an interesting question. It turns out that the thyroid hormone receptor interacts with a form of the retinoic acid receptor in cells. Both receptors function to control lipid metabolism.

Q. Would that explain why some people with hypo- or hyperthyroid activity are thin or fat?

A. Perhaps. We first used cells that had the capacity to differentiate from fibroblasts—cells in connective tissue—to adipocytes or fat cells. We found that none of the cells responded to thyroid hormone, which prompted us to look at retinoic acid regulation of adipocyte function. That's when we found a retinoic acid regulatory scheme. While interesting, the implications of this finding to human health remain unclear.

Q. Could deficiencies in vitamin A in certain areas of the world affect lipid metabolism?

A. Possibly.

Q. You've published a long series of papers on how dietary fats affect liver genes that regulate endogenous fatty acid synthesis and oxidation. Which dietary fats are important in these effects?

A. All types of dietary fats affect liver metabolism and gene expression. Saturated fats promote fatty acid synthesis, while polyunsaturated fats inhibit fatty acid synthesis and promote fatty acid oxidation. Human diets typically contain more saturated and monounsaturated fats than polyunsaturated fats.

Q. What are the differences between saturated, monounsaturated, and polyunsaturated fats?

A. The term saturation refers to the absence of chemical double bonds between carbon atoms in the fatty acid chain. The fatty acid is "saturated" with hydrogen atoms. Saturated fatty acids tend to have a more rigid structure. Unsaturated fatty acids have at least one double bond. The flexibility of that fatty acid increases as the number of double bonds increases. Monounsaturated fatty acids have one double bond; polyunsaturated fatty acids have two or more double bonds. The bulk of fatty acids are found in cell membranes and storage lipids, like triglycerides. Fatty acids in membranes affect the structure and function of the membrane. A bulky lipid—an unsaturated fat—or a non-bulky lipid like a saturated fat will influence the structure of the membrane and the function of proteins imbedded in membranes differently. There are many receptors in plasma membranes that communicate environmental signals to the inside of the cell. As the nature of the lipids in membranes changes, the function of these receptors and the control of cell function also change.

Q. That suggests that there is an optimum concentration of the various types of fats in the body to maintain proper membrane fluidity and function.

A. Yes, but that optimum concentration is likely to be influenced by gender, age, genetic background, and health status.

Q. What about trans fat?

A. Trans fat is unsaturated fat, but the double bond is in a different configuration. There are two fundamental configurations for double bonds, either trans or cis. Natural double bonds in corn oil are in the cis configuration, whereas the hydrogenation of corn oil produces fatty acids with the trans configuration. Unsaturated fats with the trans configuration behave more like saturated fats.

Q. Do trans fats occur naturally in our diet or do they come mostly from processed products?

A. Ruminants generate trans fats during the process of food digestion. Ingesting dairy products or meat from ruminants will increase the dietary intake of trans fats. Processed foods containing "hydrogenated vegetable oil" or "partially hydrogenated vegetable oil" are another source of dietary trans fats.

Fatty Acids Figure

Q. What is the difference between n-3, n-6, and n-9 fatty acids?

A. The number refers to the location of the double bond in the molecule. Fatty acids have a carboxyl end and a methyl end—the alpha and the omega, respectively. In n-3 fatty acids, the double bond is three carbons from the methyl end. An n-6 fatty acid has the double bond six carbons away, and in an n-9 fatty acid, the double bond is nine carbons away from the methyl end.

Q. What foods contain n-3, n-6, and n-9 fatty acids?

A. All of the plants in our diet have varying amounts of the saturated and unsaturated fatty acids of the various classes that we just discussed. The predominant n-3 fatty acid in plants is alpha-linolenic acid. It's found in soybean oil, canola oil, and walnuts. Olive oil contains n-9 fatty acids like oleic acid. Linolenic and alphalinolenic acids are essential fatty acids that we have to get from our diet in order to make longer chain polyunsaturated fatty acids that are very important in biological functions—the long chain, highly unsaturated n-3 fatty acids are found in salmon, other cold water fish, and in fish oil supplements (anchovy oil). These are known to be cardioprotective and control blood lipids.

Q. The brain contains a lot of n-3 fatty acids, which also affect cognition, mood, and learning. Since the fats found in most dietary plants are not efficiently converted to n-3 forms in our bodies, does this suggest that early humans consumed lots of fish?

A. This is an interesting question. There is some evidence suggesting that humans in the plains of Africa migrated to the coast. Once there, they would have had more access to fish that are enriched in very long chain n-3 fatty acids. Dietary conversion of alpha-linolenic acid to n-3 fatty acids like eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids is slow but effective. Vegetarians who consume plants with n-3 fatty acids don't have unusual health problems. Also, certain tissues maintain their lipids despite significant variation in diet.

Q. Are sufficient amounts maintained because of the slow turnover and slow loss in the brain and nervous tissue?

A. That is one interpretation, but more study is required to assess mechanisms controlling tissue-specific synthesis and turnover of polyunsaturated fatty acids, for example, in the central nervous system.

Q. Polyunsaturated fats, or PUFAs, are important in energy metabolism, for cell structure, and as regulators of gene expression, especially those that control n-9 fatty acid synthesis. What do n-9 fatty acids do in the body?

A. N-9 fatty acids are monounsaturated fats found in olive oil, for example, and also synthesized in the body from glucose. They are very important for making storage lipids like triglycerides. An early step in making triglycerides is adding oleic acid to glycerolphosphate. Triglycerides are the main storage form for lipids in adipose tissue in our bodies. Elevated triglycerides in the blood are an independent risk factor for cardiovascular disease.

Q. Why do elevated triglyceride levels contribute to heart disease?

A. Good question! High blood triglyceride levels may be a marker for abnormal or ectopic storage of lipids in tissues. Accumulating triglycerides in muscle, liver, and other tissues induces inflammation and insulin resistance, resulting in type-2 diabetes. Type-2 diabetes is a risk factor for cardiovascular disease.

Q. How do n-3 fatty acids suppress triglycerides?

A. N-3 fatty acids like the ones in fish oil inhibit the synthesis of triglycerides by lowering the cellular level of substrates for triglyceride synthesis. This is achieved by inhibiting fatty acid synthesis and enhancing fatty acid oxidation.

Q. Do n-6 fatty acids promote insulin resistance?

A. The short answer is no. In general, the n-3 and n-6 polyunsaturated fatty acids are beneficial in the prevention of chronic disease. However, too much, or an imbalance of n-6 versus n-3 fatty acids may cause health problems. Our modern diets provide too much n-6 and not enough n-3 fatty acids. The n-6 fatty acids are precursors to inflammatory lipids. And inflammatory lipids play an important protective role in many biological functions that are very important. When n-6 fatty acids are in excess, they tip the balance to a point of enhanced inflammation within the tissue.

Q. Is that mediated by prostaglandins?

A. Yes, mainly eicosanoids. Prostaglandins, leukotrienes, and thromboxanes are all made from these fats and have a wide variety of functions. For example, prostaglandins are synthesized in almost all cells. These eicosanoids control platelet aggregation, calcium flux, hormone regulation, cell growth, metabolism, vasodilation, bronchodilation, and other functions. Isoprostanes are eicosanoids made from the free-radical mediated peroxidation of the n-6 fatty acid, arachidonic acid, and have been used as biomarkers of oxidative stress.

Q. Which fatty acids are anti-inflammatory?

A. N-3 fatty acids—the fish oils.

Q. How do dietary fats affect the retinopathy that can accompany diabetes?

A. Diabetic retinopathy is a problem with the vascular system of the retina; it is similar to atherosclerosis. Diabetic retinopathy involves enhanced storage of lipids and a loss of vascularity within the retina.

Q. Do dietary fats influence tumorigenesis and, if so, how?

A. The impact of dietary fat on tumorigenesis is controversial. There are studies in animals suggesting that n-6 fatty acids promote the progression of colon cancer, while n-3 fatty acids attenuate the development of colon cancer.

Q. Is there any evidence that dietary fats affect tumor growth in people?

A. At this time, the evidence is not compelling. There are nearly 90 clinical trials investigating the impact of dietary fat on cancer. In contrast, excess body fat is a risk factor for numerous cancers.

Q. Is there much evidence that fish oil supplementation is beneficial?

A. There are over 470 clinical trials—ongoing or completed—investigating the impact of n-3 fatty acids on human health. There is certainly a lot of interest in these fats and their impact on health and disease. Many scientists are trying to find out if studies carried out in cell culture and animals are applicable to humans. N-3 fatty acids are clearly beneficial in the control of blood triglyceride levels and in cardioprotection. These clinical trials may reveal beneficial effects of n-3 fatty acids on other processes, like inflammation and cognitive function.

Q. Are the doses used in these animal studies greater than what people would consume in a diet that includes fish?

A. Typically, yes. And in some cases they are biased toward a particular kind of n-3 fatty acid. In our studies on fatty liver disease, we look at the effect of EPA, DHA, and a combination of EPA and DHA. Most fish oil capsules contain a combination of EPA and DHA, and the ratio of these two is highly variable depending on the source.

Q. Do you recommend supplementation with fish oil?

A. Yes. Before taking fish oil, consult with your physician to be sure that there is not some underlying problem, such as increased bleeding time. Aspirin, vitamin E, and a drug called Plavix inhibit platelet aggregation, which is a key event in blood coagulation. If you take these compounds and use fish oil, you may significantly increase the time it takes to stop bleeding. If someone is taking an anticoagulant or planning surgery, they should discontinue use of fish oil supplements.

Q. The ratio of the intake of n-6 to n-3 fatty acids has changed dramatically over the past few generations as our diets have changed. Do we know anything about the optimal ratio?

A. In general, a high n-6 to n-3 ratio is considered pro-inflammatory. More studies are required to define the optimal ratio.

Q. Do you think that consuming fatty fish a couple times a week is equivalent to taking a fish oil supplement or is it better to take a fish oil supplement regularly?

A. I think a supplement is probably better for health because itís more uniform and continuous.

Q. If one chooses to take a fish oil supplement, what criteria are important in making the selection?

A. Look at the composition of the fatty acids on the bottle and make sure that it has a level of DHA and EPA that is consistent with cardiovascular protection—about 500 mg of combined DHA and EPA per day—as an absolute minimum.

Q. How does EPA or DHA influence the risk for strokes and heart attacks?

A. That is complicated and related, in part, to the control of blood lipid levels. Generally, fish oils lower triglycerides but may elevate cholesterol in some individuals. Consumption of fish oil changes the characteristics of the polyunsaturated fatty acids within the arterial wall so that they may be less prone to cause inflammation. Membrane lipids contain both n-6 and n-3 fatty acids. If those are predominately n-6 fatty acids, which are substrates for making eicosanoids, then membrane phospholipid metabolism by phospholipases generates n-6 fatty acids that enter the prostaglandin synthesis pathway and produce inflammatory eicosanoids. Membrane-associated n-3 fatty acids are less likely to be cleaved out of membrane phospholipids. Moreover, n-3 fatty acids are poor substrates for enzymes that generate prostaglandins. So fish oil has the potential to reduce inflammation by lowering the production of inflammatory eicosanoids.

Q. How does alpha-linolenic acid from walnuts, for example, benefit cardiovascular health?

A. The benefit gained from alpha-linolenic acid is that it is a precursor to DHA and EPA. However, alphalinolenic acid is not as efficacious in cardioprotection as DHA and EPA. Thus, supplementing the diet with DHA and EPA provides better cardioprotection.

Q. Some large-scale epidemiological studies found that walnut consumption, which is rich in alpha-linolenic acid, was associated with decreased risk for atrial and ventricular fibrillation (cardiac arrhythmia).

A. Again, that probably relates to the conversion of alpha-linolenic acid to EPA and DHA, which are anti-arrhythmic.

Q. There is a lot of interest in the obesity epidemic among children and adults in America. How would you gauge the contribution of dietary fats or carbohydrates to this?

A. Simple carbohydrates like sugar and calorically dense, high-fat foods contribute to the problem, as well as a lack of exercise. Thereís ongoing debate about the relative importance of simple carbohydrates and dietary fats in obesity. For a long time, we thought that carbohydrates like simple sugar (glucose, fructose, and sucrose) were not well converted to fat in humans. We now know that's not true. There is a reasonable amount of scientific evidence that elevated carbohydrate intake will contribute to increased fat deposition. The body has only so much capacity to store carbohydrates, and it does so in the form of glycogen. If you fill up the glycogen pool, the rest becomes fat. Dietary fat, on the other hand, is also very important because of the nature of the fat that we eat, which tends to be more biased toward saturated and monounsaturated fats and less polyunsaturated fats, resulting in imbalances in the distribution of fat in tissues.

Q. Last summer the media reported your discovery that diabetic mice could be cured by manipulating a gene that makes a fat-metabolizing enzyme. How does that work? Is there any way to increase that enzymatic activity in humans?

A. First of all, the term "cure" was media hype. Our work may have promise for an alternative method to treat some diabetic complications. Humans with metabolic syndrome and obese mice that have characteristics of metabolic syndrome have a polyunsaturated fat profile in blood that is different from normal, healthy humans or mice. A large number of enzymes in the liver participate in the production of polyunsaturated fatty acids. We examined the effect of obesity and diabetes on these enzymes and found that one enzyme, called elongase-5, had decreased levels of activity in livers of fat mice. We then restored fatty acid elongase to normal levels in livers of obese, diabetic mice; this treatment corrected the hyperglycemia and fatty liver, but did not correct the obesity. In other words, the mice were obese, but no longer diabetic.

Q. How did you raise the enzyme levels in the livers of the mice?

A. We used an adenovirus-mediated gene therapy approach to elevate expression of the enzyme. We engineered an adenovirus to contain the gene expressing fatty acid elongase-5. Infection of mice with the adenovirus leads to the expression of the enzyme in the liver and no other tissue. The liver starts making more of the enzyme within 24 hours after infection.

Q. Are there compounds that raise the enzyme level in the liver?

A. Our studies in mice have shown that fibrates increase the expression of this enzyme. Fibrates are used to manage dyslipidemia in humans; fibrates lower blood levels of cholesterol and triglycerides.

Q. Do you have any dietary recommendations for the prevention or treatment of diabetes with respect to fatty acids?

A. The American Diabetes Association (www.diabetes.org) has an excellent Web site for this information. If your body mass index (BMI) exceeds 30, you may develop diabetes and metabolic syndrome as you grow older. I think dietary supplements of n-3 fatty acids are prudent for just about everybody as long as they are not on an anticoagulant therapy.

Q. What are your plans for future research?

A. We have two major projects under way in the lab. In one, we are investigating the use of n-3 fatty acids as a way to prevent the development of fatty liver associated with diet-induced obesity. The second line of investigation is a continuation of the "gene therapy approach" described above. We are defining the mechanism used by polyunsaturated fatty acids to control diabetic complications.

Last updated July 2011