The Center for Botanical Lipids

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Reviews, science, clinical trials, effectiveness, safety and more

NCCAM and ODS Co-Fund Five Botanical Research Centers

NIH News Release May 2005

Five dietary supplement research centers focusing on studies of botanical products have been jointly funded by the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (ODS), both components of the National Institutes of Health (NIH). Research conducted by these centers will advance
... read more

Scientists to Study Actions of Botanical Oils Including Flaxseed and Borage

ImmuneSupport.com April 2005

Wake Forest University School of Medicine has received a $7.5 million grant from the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (ODS) to open a research center to study dietary supplements ... read more

Institute of Medicine provides advice of benefits of eating seafood

Americans eat seafood in a variety of forms, but mixed messages have confused the public about the relative safety of eating seafood. A recent report from the Institute of Medicine provides advice on the relative cardiovascular benefits of eating fish vs the potential toxins that fish may contain. Read a summary of the original report here or read more of this article here.

Welcome to Articles for Everyday People

In this section we will present brief reviews and commentary on recent reports in the scientific literature and in the press. The goal of this section is to summarize, in lay language, the current scientific thoughts and debates on recent discoveries in dietary lipids, botanicals, and supplements. These topics will naturally intersect topics of nutrition, exercise, and inflammation. References are included to assist the reader who wishes to learn more about each of these topics or examine the original reports.

These articles are for information only, and should not be interpreted as endorsement of any particular product or dietary practice. Consult your physician before any use of dietary supplements (see FAQs for comments on potential side-effects of some botanicals or supplements). Other limitations apply; see our Website Access Agreement.

2nd Annual Symposium Scheduled for October - Call for Abstracts until Sept 7

Recruiting Healthing Adult Volunteers for a Dietary Fatty Acid Research Study

8/17/2007

The Center for Botanical Lipids is recruiting healthy adult volunteers for a research study on the mechanisms by which borage oil and fish oil reduce inflammation. This study will take place at Wake Forest University School of Medicine.

Student at centrifuge

Call For Abstracts to the 2nd Annual Symposium on Dietary Fatty Acids

The Center for Botanical Lipids at Wake Forest University School of Medicine will host the 2nd Annual Symposium on “The Role of Dietary Fatty Acids in the Prevention and Treatment of Disease”. The program will run from Wednesday evening, Oct 24, until noon on Friday, Oct 26, at Tanglewood Park near Winston-Salem, NC.

THE ABSTRACT DEADLINE HAS BEEN EXTENEDED TO OCTOBER 2nd.

For more information or to request a registration form please email your request to cbl@wfubmc.edu. Please include you name, institution, academic title, and email address. Or you may access the registration materials below by opening the attached files.

This years featured speakers include:
William Harris (Disease Research Institute, University of South Dakota)
Arthur Spector (Department of Biochemistry, University of Iowa)
Larry Rudel (Department of Pathology, and the Center for Botanical Lipids, Wake Forest University School of Medicine)
Jay Whelan (Department of Nutrition, University of Tennessee-Knoxville)

Jonathan Arm (Division of Rheumatology, Immunology and Allergy, Brigham & Women's Hospital of Harvard University) will conduct a workshop on dietary fatty acid preclinical studies.

Student and postdoctoral abstracts will be favored for oral and poster presentations.

Registration_form.pdf
Registration_form.doc
Information_sheet.doc
Botanical_Lipids_Symposium_NEW.pdf

WELCOME!

Wake Forest University Health Sciences, in collaboration with the Brigham and Women's Hospital, a Teaching Affiliate of Harvard Medical School, has established a NIH funded Center for Botanical Lipids. The central objective for this new research Center is to determine the safety and effectiveness of fatty acid-based dietary supplements for the prevention and treatment of chronic inflammatory diseases such as atherosclerosis and asthma.

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.

MEDIA CONTACT

By Mail:
The Wake Forest & Brigham and Women's Center for Botanical Lipids
Wake Forest University Health Sciences
Department of Physiology and Pharmacology
Medical Center Boulevard
Winston-Salem, NC 27157

By Email:

CONTACT US

ABOUT OUR STAFF

The staff of the Center for Botanical Lipids is comprised of four research laboratories and two cores. The Administrative Core, the Lipid Analytical Core, and the research projects of Dr. Larry Rudel, Dr. John Parks, and Dr. Ski Chilton are housed in the new Biotechnology Research Facility 1 (BRF1), a part of Wake Forest University Health Sciences located in the Piedmont Triad Research Park in downtown Winston-Salem, NC. The research project of Dr. Jonathan Arm's laboratory is located in the Division of Rheumatology Immunology and Allergy at the Brigham and Women's Hospital in Boston.

Drs. Rudel and Parks (Projects 1 and 2) are experts in lipid dysfunctions associated with vascular diseases such as atherosclerosis. Drs. Chilton and Arm are experts in the regulation of lipid mediator generation and their roles in inflammation. The Center combines this expertise to focus on the basic molecular and cellular actions of botanical oil supplements for the prevention and treatment of inflammatory diseases.

The new BRF1 building also houses the Lipid Sciences program of the Department of Pathology and several laboratories of the Department of Physiology and Pharmacology. Consequently, this location combines over 50 years of expertise in lipids and human health and serves as a vital resource for the success and development of new ideas in botanical lipids research.

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The information on this Website is provided for general informational purposes only and SHOULD NOT be relied upon as a substitute for sound professional medical advice, evaluation or care from your physician or other qualified healthcare provider. Nothing on this Website should be used for treating or diagnosing a medical or health condition or for replacing any relationship with your physician or other qualified healthcare provider. The health information furnished on this Website and the interactive responses (if any) furnished by or through, this Website are not intended to or implied to be professional medical advice. You are encouraged to consult other sources and confirm the information contained within this Website. Consult your own physician regarding the applicability of any opinions or recommendations with respect to your symptoms or medical condition. For medical concerns, including decisions about medications and other treatments, you should always consult your physician or other, qualified healthcare professional. In serious cases, seek immediate assistance from emergency personnel. If you have or suspect that you have a medical problem or condition, please contact a physician or other qualified healthcare provider immediately. YOU SHOULD NEVER DISREGARD MEDICAL ADVICE OR DELAY IN SEEKING IT BECAUSE OF SOMETHING YOU HAVE READ ON THIS WEBSITE. No medications, diet supplements or treatments as may be described on this Website should be taken or begun without first consulting your physician or other healthcare provider. No information on this Website should be considered or shall be deemed to be an endorsement or recommendation by Wake Forest University Baptist Medical Center (the Medical Center) of any medication, diet supplements, treatments, products, tests or otherwise.

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This Agreement is subject to change without notice.

Reprinted from WFUSOM Web Site Access Agreement.

Center for Botanical Lipids scientist cited among “top breakthroughs” of the year

Wake Forest University School of Medicine - News Release, Dec. 2006

Larry Rudel, PhD, a Center for Botanical Lipids scientist and project leader, has been cited as having one of two research projects at Wake Forest University School of Medicine that were named "top breakthroughs of the year" by Discover magazine. The January 2007 issue of Discover credits Dr. Rudel with the No. 14 science breakthrough (No. 2 in Medicine) for his research linking dietary trans fatty acid intake with increased abdominal fat and with the correlated increased risks for diabetes and heart disease. Trans fats are man-made, partially hydrogenated vegetable oils, popularly used in many commercial fryers, cookie and cracker production because of the stability and physical properties of the fats. Recent data from several studies demonstrating the ill effects of trans fats on human health has lead to increasing federal and state regulation on their use and has stimulated a search for healthy alternatives.
Read news release.
Read Discover article

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WEBSITE ACCESS AGREEMENT for THE CENTER OF BOTANICAL LIPIDS & WAKE FOREST HEALTH SCIENCES

NO MEDICAL ADVICE

NO WARRANTIES

OFFENSIVE OR EXPLICIT CONTENT

DISCLAIMER OF ENDORSEMENT

AGREEMENT NOT TO ACCESS UNAUTHORIZED SITES

As an additional condition to accessing this Website, you agree not to attempt to gain unauthorized access to any areas of this Website, computer systems or networks connected to this Website.

AGREEMENT NOT TO VIOLATE COPYRIGHT

Natural Living

38.2 million American adults (about 19 percent) use non-vitamin, non-mineral natural products; primarily botanical supplements. Polyunsaturated fatty acids (PUFAs) are one of the largest growing groups of dietary supplements consumed.

A recent analysis examining fish consumption and coronary heart disease combined data from 13 of the larger studies (~220,000 people) and indicated that fish consumption decreased coronary heart disease as well as sudden cardiac deaths. (He et al., Circulation 109:2705

Research & Statistics

Recent reports indicate that the incidence of specific diseases characterized by inflammation is increasing. This is pronounced in countries with "western diets". Similarly, dietary supplement use is also increasing, often faster than scientific evidence identifies the mechanisms by which such supplements may or may not work. The potential link between these trends suggests that people are aware of these changes, but that much remains to be learned about which dietary supplements are beneficial and how they should be used. The data below are a snapshot of some of the recent trends.

Inflammation Epidemic

More than one in three US Citizens will suffer from an inflammatory disease.

Asthma: more than 20 million Americans have asthma today, twice as many as in 1980. American Lung Association. Epidemiology & statistics Unit, Research and Program Services. Trends in Asthma Morbidity and Mortality May 2005, reviewed at http://www.aaaai.org
Allergies: More than 50 million - 20% of the US population, suffers from allergies; there has been a 100% increase (doubling) in the prevalence of hay fever in developed countries in each of the last three decades. American Academy of Allergy, Asthma and Immunology (AAAAI). The Allergy Report: Science Based Findings on the Diagnosis & Treatment of Allergic Disorders, 1996-2001, reviewed at http://www.aaaai.org
Diabetes: Nearly 21 million Americans have diabetes, causing approximately 200,000 deaths per year in the US. http://www.diabetes.org
Cardiovascular Diseases: Causing over 900,000 deaths in the US in 2003, over 71 million Americans having some form of cardiovascular disease. http://www.americanheart.org
Obesity: Over 64% of American adults are overweight or obese; 16% of children are overweight or obese and twice that many are at risk. (Hu et al., JAMA, 2002, 287:1815-1821.

Our Childrenâ€™s Health

Asthma prevalence, hospitalizations, and asthma deaths among children have increased steadily between 1980 and 1998. (Akinbami and Shoendorf. Pediatrics, 2002, 110:315-322)

Shifts in Modern Western Nutrition

Prior to 1800: Prior to 1800, ~ 20% of the western diet was fat and the amounts of omega-6 and omega -3 fatty acids was balanced ~1:1
Since 1800: Total fat in the diet has increased to over 30%, omega-6 fatty acids have increased and omega-3 fatty acids have decreased, driving the ratio to greater than 7:1 in favor of the mostly proinflammatory omega-6 fatty acids (Simopoulos. World Rev Nutri Diet, 2005,95:80-92)

About the Center for Botanical Lipids

Wake Forest University Health Sciences has established the Center for Botanical Lipids. This central objective for this new research Center is to determine the role of fatty acid based dietary supplements in the prevention and treatment of chronic human diseases associated with inflammation. This will include investigations into the molecular mechanisms of action, the safety, and the efficacy of Botanical Lipid dietary supplements. Nearly 20% of Americans use dietary supplements, many of them botanicals, but scientific evidence for their safe and effective use in the prevention or treatment of human diseases has lagged behind the use of the products.

This new research initiative is funded by grants from the National Center for Complementary and Alternative Medicine (NCCAM) and the Office of Dietary Supplements (ODS), which are components of the National Institutes of Health (NIH). The Wake Forest Center for Botanical Lipids is one of five such dietary supplement research centers funded through the NIH (see News and Announcements). The focus of these centers is to conduct research to establish evidence regarding the safety, effectiveness, and mechanisms of action of botanicals. Each Center specializes on a different set of botanicals and human diseases.

The Center for Botanical Lipids will utilize state of the art biochemical and clinical testing to determine the mechanism(s) of action of several promising lipid-based botanicals. The goal of this research is to identify potential new fatty acid based strategies to prevent or treat human diseases with inflammatory components. The botanicals under study include flaxseed oil, borage seed oil, and echium seed oil, all sources of specific fatty acids of interest. The Center will carry out four main research projects and operate core support laboratories.

The Wake Forest Center for Botanical Lipids operates on two campuses. The Wake Forest University Health Sciences home for the Center for Botanical Lipids is the new Biotechnology Research Facility 1 (BRF1) in the Piedmont Triad Research Park located in downtown Winston-Salem, NC (..read more). The new building was dedicated May 16, 2006, in a ceremony featuring a keynote address by Dr. Elias A. Zerhouni, Director of the National Institutes of Health, who also spoke at the Wake Forest University School of Medicine Graduation. BRF1 also houses the Lipid Sciences Research Program, a 50-year research effort at the medical school from which the Center for Botanical Lipids has grown. BRF1 is the sixth addition to the Piedmont Triad Research Park, a planned 240-acre Research Campus. The projects of Dr. Floyd (Ski) Chilton, Dr. Larry Rudel and Dr. John Parks are housed in BRF1, bringing together faculty from Departments of Physiology/Pharmacology with the Department of Pathology/Lipid Sciences. The second campus site is at the Brigham and Women's Hospital, a Teaching Affiliate of the Harvard Medical School. That campus is the site of the asthma project lead by Jonathan Arm, M.D, who is a member of the Inflammation and Allergic Disease Research Section of the Division of Rheumatology, Immunology and Allergy at the Brigham and Women's Hospital.

Jonathan P. Arm, M.D.

WELCOME

ABOUT OUR STAFF

Analysis of macrophage-specific Abca1

July 2-7

John Parks, PhD, Professor of Pathology/Lipid Sciences, PI of Project 2
presented "Analysis of macrophage-specific Abca1
knockout mice" as an invited Speaker and Session Chair at the Lipoprotein
Gordon Conference, Mount Holyoke College, South Hadley, MA.

Q. What is an inflammatory disease?

A. Inflammatory diseases-- diseases where the body's own defense system turns against itself-- are growing in record numbers in the US and other western countries. Chronic inflammation is suspected or known to be a principle trigger for over 30 conditions and diseases including rheumatoid arthritis, asthma, allergies, diabetes, cancer and Alzheimer's.

Q. Is inflammation a bad thing?

A. Not all inflammation is necessarily bad. Inflammation is part of the body's normal immune function, which acts as a defense system against bacteria, viruses, tumor cells, and other conditions. Inflammatory diseases build on an imbalance of the immune response. The immune system may fire too quickly or too aggressively or both, or other checks and balances in the system may be altered by the disease process (genetics or environmental effects). The combined result is disease with a significant inflammatory component.

Q. Medicines help people with inflammatory diseases like arthritis. Can medicine be replaced by diet?

A. By no means. Medicines are lifesavers for millions of people. Medicines relieve pain and restore quality of life for sufferers of a variety of inflammatory diseases. However, medications may not act for everyone, may act incompletely, and may carry unwanted side effects. There is not a complete drug solution for inflammatory diseases. Dietary lipids can impact the production of inflammatory mediators and impact disease progression and severity as shown in many of the cardiovascular studies. Diet is an integrative strategy, not an alternative one. Loosing weight, believe it or not, is another great way to fight inflammation.

Q. Fish and plant oil supplements are natural products, but is there any harm in trying them on my own?

A. You need to check with your doctor before starting a regimen with dietary supplements. They could affect medications you are already taking. You need them in the right quantity and quality if they are to be effective. However, you can't go wrong by eating good foods.

Q. What do you mean by the quality of the supplement?

A. The quality of dietary supplements is especially important, as they are often extracted from natural plant materials and could contain natural toxins or environmental contaminants. For our Center research projects, we verify the quality and quantities of chemical compounds in each research extract (see Projects - Core A). Manufacturers of commercial products can supply quality assurance data on their products. For more specific information on natural toxins in plant material extracts, see the excellent information at Memorial Sloan-Kettering Cancer Center.

Q. What is the main culprit in inflammatory disease?

A. A number of factors come together to cause inflammatory diseases. The dramatic influence of the increase in obesity, diets lacking in proper ratios of omega 6 and omega 3 fatty acids, lacking in fiber, and the lack of exercise in most Americans are among the contributing causes of inflammatory diseases. Of course, genetics and environment play a role, but dietary lipids can modulate the course of inflammatory diseases.

Q. What is the main defense against inflammatory disease?

A. Many medicines (anti-inflammatory drugs) can help with the signs and symptoms of the disease. But changing the diet to eliminate the foods that can drive inflammation and add foods (such as omega-3 fatty acids) that reduces inflammation can be essential. The best documented examples of this are in cardiovascular diseases which are reduced in populations consuming fish (fish oils containing omega-3 fatty acids which are rich sources of GLA and EPA).

Q. Are there any cautions about the dietary supplement use of GLA or EPA?

A. GLA (gamma-linolenic acid) needs to be balanced with the proper amount of EPA (eicosapentaenoic acid). Taking high levels of GLA without the right amount of EPA may lead to some of the GLA going being metabolized in the liver to form arachidonic acid (AA), a key inflammatory messenger. This could worsen inflammation.

Q. Where can I look for more information?

A. There are many great places to learn more. This and other NIH Botanical Center sites will connect you to many of those places.

The Role of Omega 3 Fatty Acids on Vascular Biology, Vascular Inflammation, Hypertension, Dyslipidem

November 16th

Floyd (Ski) Chilton, PhD presented "The Role of Omega 3 Fatty Acids on Vascular Biology, Vascular Inflammation, Hypertension, Dyslipidemia, and Cardiovascular Disease" at the 11th Annual Hypertension Symposium in Nashville, TN.

Cholesterol Esterification in Heart Disease

November 8th

Larry Rudel, PhD, presented "Cholesterol Esterification in Heart Disease" as the General Clinical Research Center Seminar, Wake Forest University Health Sciences, Winston-Salem, NC.

Fish in diet may help maintain heart rhythm

Reuters. Aug 16, 2006.

"Eating tuna or other broiled or baked fish appears to have a beneficial effect on the electrical system of the heart, which may help prevent life-threatening heart rhythm disorders, according to new reports." The mechanisms responsible for this association were unknown. However, evidence from animal studies has suggested a direct effect from fish oil intake on the hearts electrical circuitry.
... read more

The Office of Dietary Supplements Surveys Dietary Supplement Education at Nation’s Academic Institut

The ODS will survey dietary supplement education in the nation's academic institutions in the fall of 2006. The purpose is to evaluate the level and impact of focused instruction on dietary supplements that occurs in health-professional programs. This is part of an ODS initiative to expand the cadre of scientists qualified to execute research investigations on dietary supplements.
... read more

Ban on trans fats could lead to food fight

Associated press, Oct 2, 2006

Proposals in New York city proposal to ban use of unhealthy trans fats in restaurants has brought attention to a national fight over the safety of America's food supply. States and a few cities have been bold about mandating warning labels for potential hazards such as lead in candy, mercury in fish and pesticides in vegetables.
... read more

Alternative Therapies Big Business For Medical Schools

Winston Salem Journal August 2005

Researchers in field for education, not for money, a manager says ... read more

Fatty acid induced gene expression in humans

November 1-3rd

Kelly Weaver, Molecular Medicine graduate student working on project 3, presented "Fatty acid induced gene expression in humans at the 41st Annual Southeastern Regional Lipid Conference, Cashiers, NC. Co-authors were Priscilla Ivester, Arta M. Monjazeb, Kevin P. High, and Floyd (Ski) Chilton, all of Wake Forest University School of Medicine.

Trans Fatty Acids: Their Influence on Sugar and Fat in CHD

October 30-31

Larry Rudel, PhD, presented "Trans Fatty Acids: Their Influence on Sugar and Fat in CHD" to the 2006 Pennington Scientific Symposium, Botanicals and Cardiometabolic Risk, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA. Dr. Rudel served as a symposium co-chair.

The Role of Dietary Fatty Acids in Prevention and Treatment of Inflammatory Disease

October 26th

Floyd (Ski) Chilton, PhD, presented "The Role of Dietary Fatty Acids in Prevention and Treatment of Inflammatory Disease" to the Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA.

A Practical Approach to Today’s Treatments for Dyslipidemia: Newly Diagnosed Patients

October 25th

Larry Rudel, PhD, presented "A Practical Approach to Today's Treatments for Dyslipidemia: Newly Diagnosed Patients" to the Cardiology Fellows Seminar at Wake Forest University Health Sciences, Winston-Salem, NC.

Pilot Projects

A Pilot Project Program has been established by the NIH to facilitate continued growth of the core group of scientists and projects within the NCCAM and ODS Botanical Research Centers. For The Center for Botanical Lipids, the Pilot Project grants are solicited from within the Wake Forest University System and must be relevant to the Center theme and research goals (Dietary Botanical Lipid Supplements). Projects are encouraged to utilize the collaborative strengths of the four research programs and the lipid analytical core laboratory within the center. The primary purpose of this support is to attract promising investigators to the centers and provide an opportunity for them to generate sufficient preliminary data to enhance the submission of new applications for peer-reviewed research.

The first cycle of applications has been solicited, reviewed by the internal Pilot Grant Review Committee and approved by the External Advisory Committee of the Center for Botanical Lipids, with the approval of ODS and NCCAM. Eleven excellent research projects were submitted and reviewed, and two have been selected for funding for this first cycle of awards.

2006-2007

Charles Morrow, Ph.D. - Wake Forest University Health Sciences, Department of Biochemistry. Role of lipid composition on MRP1 function and response of cells to isothiocyanates chemopreventive agents.

Steve Messier, Ph.D. - Wake Forest University, Department of Health and Exercise Science. Fatty acids, Arthritis, and Inflammation in the Elderly (FAME).

2007-2008

Kylie Kavanagh, D.V.M. - Wake Forest University Health Sciences, Department of Pathology. Maternal consumption of natural botanical lipids are beneficial in in utero and neonatal programming of adult obesity and insulin resistance as compared to lipids in current western diets.

Qing Yang, M.D., Ph.D. - Wake Forest University Health Sciences, Department of Pediatrics/Neonatology. Omega-3 PUFA and Necrotizing Enterocolitis.

Internal Steering Committee

Floyd H. (Ski) Chilton, Ph.D.
Professor of Physiology and Pharmacology
Director, Wake Forest Center for Botanical Lipids
Wake Forest University School of Medicine

Lawrence L. Rudel, Ph.D.
Professor of Pathology (Director of Lipid Sciences), and Biochemistry
Wake Forest University School of Medicine

John S. Parks, Ph.D.
Professor of Pathology (Lipid Sciences)
Director of Molecular and Cellular Pathobiology PhD Program
Wake Forest University School of Medicine

Jonathan P. Arm, M.D.
Professor of Rheumatology, Immunology and Allergy
Associate Director of Allergy and Immunology Training Program
Brigham and Women's Hospital, Harvard University, Boston

James E. Smith, Ph.D.
Professor and Chairman of Physiology and Pharmacology
Wake Forest University School of Medicine

Robert Wykle, Ph.D.
Professor of Biochemistry
Wake Forest University School of Medicine

External Advisory Committee

External Advisory Board Meeting: L-R, Arthur Spector, Larry Rudel, John Parks, Curt Furberg, Ski Chilton, Bradley Undem, Jonathan Arm, Michael Aschner

Curt Furberg, M.D.
Senior Advisor to the Dean and Professor Public Health Sciences
Wake Forest University Health Sciences

William Harris, Ph.D., F.A.H.A.
Professor of Medicine,
University of South Dakota Sanford School of Medicine
Director of Nutrition and Metabolic Diseases Research at the
South Dakota Health Research Foundation, Sioux Falls

Arthur A. Spector, M.D.
University of Iowa Foundation Distinguished Professor
of Biochemistry and Medicine
University of Iowa

Bradley Undem, Ph.D.
Professor of Medicine
Johns Hopkins School of Medicine Asthma and Allergy Center

Charles Serhan, Ph.D.
Simon Gelman Professor at Harvard Medical School
Director of the Center for Experimental Therapeutics and Reperfusion Injury at the Brigham and Women's Hospital

Michael Aschner, Ph.D.
Professor of Pediatrics / Professor of Pharmacology
Vanderbilt University School of Medicine

The Latest Word on Low-Fat Diets

an analysis by Ski Chilton, Ph.D.

In early 2006, the Journal of the American Medical Association released a study that overturned much of the conventional wisdom about low-fat diets. The Women's Health Initiative Dietary Modification Trial followed 48,835 post-menopausal women -- most of them overweight or obese -- for about eight years. Forty percent of the women (19,541) were instructed to decrease their consumption of fat and increase their consumption of vegetables, fruits and grains. Sixty percent of the women (29,294) were instructed to continue their usual eating habits. (1)

Compared to the usual-eating group, the low-fat group decreased its mean total fat intake by 8.2 percent, with small decreases in saturated (2.9 percent), monounsaturated (3.3 percent) and polyunsaturated (1.5 percent) fat. (1) The researchers had postulated that a low-fat diet would reduce the women’s risk of serious disease. Instead, they were stunned to find that there were no group differences in the women’s risk of coronary heart disease, cardiovascular disease, stroke, breast cancer or colorectal cancer. (1, 2, 3)

“Why was there a null finding in this study?” asked the authors of an accompanying editorial. Among the possible reasons: “The intervention reduced intakes of fats that increase risk of cardiovascular disease (saturated fat and trans fatty acids) but also of those that might be protective (polyunsaturated fats and monounsaturated fats.) (4)

This study is revolutionary in that it gets to the issue of what does high and low fat mean? The word “fat” is unfortunate because it carries negative connotations. Many people think that fat in the diet automatically translates into excess fat on the body. Of all the nutrients we take in, fat has the worst reputation, at least partly because it’s called fat. We have been taught this paradigm that high-fat is “bad” and low-fat is “good.”

What this study shows is that this is an antiquated way of thinking. It’s an important word on that subject. It reminds us that we shouldn’t lump all fats together, but understand that fats are divided into those that are potentially beneficial to human health and those that are potentially harmful. The overwhelmingly positive data on dietary fish oils and cardiovascular disease conclusively shows that some dietary fats have tremendous health benefits. Consider the Greenland Eskimos, who eat an almost 50 percent fat diet and yet have practically no cardiovascular disease, heart attacks and strokes.

Literature cited.

Howard BV. Low-Fat Dietary Pattern and Risk of Cardiovascular Disease. JAMA 2006;295;655-666.

Prentice RL. Low-Fat Dietary Pattern and Risk of Invasive Breast Cancer. JAMA 2006;295;629-643.

Beresford SA. Low-Fat Dietary Pattern and Risk of Colorectal Cancer. JAMA 2006;295;643-654.

Anderson CA. Dietary Modification and CVD Prevention. JAMA 2006;295;693-694.

The Use of Dietary Flaxseed for the Prevention of Human Disease

by Kelly Weaver

Flaxseed (also called linseed) has been a part of the human and animal diet for thousands of years. It is the richest known plant source of omega-3 fatty acids - 58% of the total fat in flax is composed of alpha-linolenic acid (LNA); however, this fatty acid is a short chain omega-3 as opposed to the long chain omega 3s found in fish oil. A number of studies have shown that flaxseed does not replace fish oil in the diet because the conversion of LNA to the omega-3 fatty acids found in fish oil is very inefficient.

Flaxseed is also a minor source of the omega-6 fatty acid linoleic acid (LA), which makes up about 14% of the total fat content. LNA and LA are essential fatty acids, meaning they cannot be made in the body and instead must be present in the diet. LNA is thought to be necessary for the proper function of cell membranes and nerve cells. In addition to LNA, flaxseed also contains soluble and insoluble fiber and lignans, which are antioxidants and estrogen precursors called phytoestrogens.

Flaxseed provides a healthy balance of omega-3 and omega-6 fatty acids, which is thought to have beneficial effects on many diseases, especially those with a strong inflammatory component, such as inflammatory bowel disease, arthritis, asthma, gout, and lupus. Flaxseed oil has been used to treat burns, acne, eczema, rosacea, and other skin disorders, and it promotes healthy hair and nails. Flaxseed has been suggested to minimize nerve damage in degenerative diseases such as Parkinson's disease and may guard against the effects of aging.

The lignans in flaxseed may also play a role in cancer treatment and prevention, especially in women with breast cancer. The phytoestrogens found in flaxseed are thought to act as "designer estrogens" and are a good supplement to regular therapy (1). In a study of women with breast cancer, those who consumed 25 grams of flaxseed oil per day saw a reduction in tumor growth compared to placebo controls (2). The LNA in flaxseed may decrease the risk of sudden cardiac death by stabilizing the electrical system of the heart and preventing potentially fatal irregularities in heart rhythm. In a study of more than 75,000 women, those who consumed more than 1.5 grams of flaxseed per day had a 46% lower risk of cardiac death than women who consumed less than 0.5 grams per day (3).

While most studies show a benefit of flaxseed oil, there have been studies which have not been positive. In 5 out of 6 epidemiological studies on prostate cancer, flaxseed was shown to increase cancer risk, and LNA is a strong growth stimulus in isolated prostate cancer cells (4). Neither of these effects has been seen with fish oil. In addition, recent studies suggest that flaxseed may increase the risk of macular degeneration or speed up the progression of the disease.

Flaxseed is available as whole seeds, ground seeds, or oil, but due to processing, the oil may contain less lignans and fiber than the seeds. The recommended dose of flaxseed oil is one tablespoon of liquid oil per day or two 3,000 mg capsules per day. Flaxseed may slow down the absorption of oral medications if taken at the same time. Flaxseed may also interact with medications such as blood thinners, statins, cyclosporine, and NSAIDS. It is important to consult a healthcare provider before using flaxseed while taking these medications.

Literature cited.

Moyer, Paula. A Muffin a Day for Breast Cancer? 2000 December 8. WebMD. http://www.webmd.com/content/article/29/1728_66150.htm

Clin Cancer Res. 2005 May 15;11(10):3828-35

Peck, Peggy. Flaxseed May Lower Sudden Cardiac Death Risk. 2004 November 8. WebMD http://www.webmd.com/content/article/96/103889.htm

WebMD. Ask Dr. Ornish. http://www.webmd.com/content/pages/3/3079_1820.htm

Use of dietary fish oils for the prevention and treatment of heart disease

an analysis by Ping Zhang, Ph.D.

Heart disease is still the number one killer in the United States and other Westernized societies. About half of the deaths from heart disease are from coronary heart disease (CHD), which includes heart attack. Heart attack happens when one or more of the coronary arteries supplying blood to the heart muscle are blocked. This is usually caused by the build up of plaques (deposits of fat-like substances), a process called atherosclerosis (2). One of the first approaches to treatment of cardiovascular disease (CVD), including heart disease, is dietary intervention to reduce saturated fat and cholesterol intake.

In addition, an increase of fatty fish consumption or the use of fish oil supplement is recommended to reduce the risk of premature heart disease. The beneficial effects of dietary fish oil on cardiovascular disease have been well-documented from both epidemiology and randomized clinical trials.

The concept that dietary fish oil protects against cardiovascular disease was based on epidemiological studies in the 1970's on disease patterns of Greenland Eskimos (4). Even though the Greenland Eskimos had a high fat diet, they exhibited very low cardiovascular mortality compared with their counterparts in Denmark. The protective effect of fish oil was attributed to the high content of two highly unsaturated omega-3 fatty acids, EPA and DHA. Following this initial observation, an epidemiological study in Japan also showed that the Japanese population, which has a higher intake of EPA/DHA in the diet relative to that of North Americans, exhibited considerably lower rates of acute myocardial infarctions (MI) (3). In addition, many epidemiological studies within populations also reported that men who ate at least some fish weekly had a lower CHD mortality rates compared to that of men who ate none (1). A recent study conducted with women in the Nurses' Health Study reported an inverse association between omega-3 fatty acids from fish and CHD death (8).

Numerous randomized trials in humans have also shown a cardio-protective role of dietary fish oil for both primary prevention and secondary prevention. The Physicians' Health Study which followed 20,551 subjects for 12 years reported an approximately 50 percent overall relative risk reduction even with a small amount of fish intake (eat fish once a month) (5). The Diet and Reinfarction Trial results indicated a 29% reduction in all-cause mortality over a two year period in male MI survivors advised to increase their fatty fish intake (6). In the GISSI-Prevention Study, 11,324 patients with preexisting CHD were randomized to fish oil, vitamin E, both, or neither treatment groups. After the follow-up for 3.5 years, the fish oil group had a 20% reduction in all-cause mortality and a 45% reduction in sudden death compared to controls (7).

Multiple mechanisms have been proposed for the cardio protective benefits of dietary fish oil. One of the most consistent observations associated with consumption of fish oil is a reduction in plasma triglycerides (TG). Dietary omega-3 fatty acids also reduce the postprandial TG response following a high fat meal. Dietary fish oil has also been shown to reduce blood pressure, decrease thrombosis, decrease arrhymias, decrease inflammation, and decrease endothelial function.

Increasing dietary fatty fish intake or taking fish oil supplements results in elevated levels of EPA and DHA in tissues. Levels of EPA and DHA in serum phospholipids reflect dietary intake and overall physiological status. Evidence has shown an inverse correlation between omega-3 fatty acids, particularly DHA levels, and the development of CHD in men. Higher DHA and total serum omega-3 fatty acids levels (more than 7.2% of total serum fatty acids) was estimated to result in an approximately 30% overall lower risk of CHD (3).

Overall most studies reported so far show evidence that consumption of fish oil reduces various CVD outcomes such as sudden death, cardiac death, non-sudden death from MI, and MI. However, some studies have not reported a beneficial association of fish oil consumption and CHD mortality. The explanation for the conflicting results is not clear by may be related to the different contents of methyl mercury and other organic toxic compound such as PCBs in certain fish that may attenuate the protective effects of dietary fish oil on cardiovascular health (1, 9).

The current dietary intake of total omega-3 fatty acids in the United States is about 1.6 g/d (about 0.7% of total energy). Of this, a-linolenic acid accounts for 1.4 g/d and only 0.1-0.2 g/d comes from EPA or DHA. Although a-linolenic acid can be converted into EPA and DHA in the body, the extent of conversion is very limited. All fish contain EPA and DHA, however the quantity varies among species and sources. The American Heart Association suggests that healthy adults eat two fatty fish meals a week for positive cardiovascular benefits (1).

Patients with CHD are encouraged to increase consumption of EPA and DHA to about 1 g/d. This level of omega-3 fatty acid consumption can be achieved through diet, but for people who do not eat fish, a fish oil supplement may be considered. Most common fish oil capsules in the United States provide 180 mg of EPA and 120 mg of DHA, thus three 1-g capsules will be roughly enough to provide 1g/d of omega-3 fatty acids (1).

Consumers should be aware of both the benefits and risks of fish and fish oil consumption. Children and women who are pregnant or lactating are at increased risk for mercury toxicity from fish consumption but are also at low risk for CHD. For this group, avoiding potentially contaminated fish is a higher priority. Men beyond middle-age and postmenopausal women are at higher risk for CHD. The benefits of consuming more fish far outweigh the risks of mercury contamination if the contaminations of fish are within FDA and EPA limits. Consumption of a wide variety of fish with contaminations within the guidelines is advised to increase omega-3 fatty acid intake.

Literature cited:

Kris-Etherton PM, Harris WS, Appel LJ; American Heart Association. Nutrition committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation 2002. 106:2747-57.

Lusis, AJ. Atherosclerosis. Nature 2000. 407: 233-241.

Holub DJ, Holub BJ. Omega-3 fatty acids from fish oils and cardiovascular disease. Mol Cell Biochem 2004. 263:217-225.

Dyerberg J, Bang HO. A hypothesis on the development of acute myocardial infarction in Greenlanders. Scand. J. Clin. Invest. 1982. 42:7-13.

Albert CM, Hennekens CH, O'Donnell CJ, et al. Fish consumption and risk of sudden cardiac death. JAMA. 1998. 279:23-28.

Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, Elwood PC, Deadman NM. Effects of changes in fat, fish and fiber intakes on death and myocardial infarction: diet and reinfarction (DART). The Lancet 1989. 2: 757-761.

GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. The Lancet 1999. 354: 447-455.

Hu FB, Bronner L, Willett WC, Stampfer MJ, Rexrode KM, Albert CM, Hunter D, Manson JE. Fish and Omega-3 fatty acids and the risk of coronary heart diseasein women. JAMA 2002. 287: 1815-1821.

Virtanen JK, Voutilainen S, Rissanen TH, Mursu J, Tuomainen TP, Korhonen MJ, Valkonen VP, Seppanen K, Laukkanen JA, Salonen JT. Mercury, fish oils, and risk of acute coronary events and cardiovascular disease, coronary heart disease, and all-cause mortality in men in eastern Finland. Arterioscler Thromb Vasc Biol. 2005. 25(1):228-33.

What About Canned Fish?

an analysis by Ski Chilton

Canned tuna is the second only to shrimp as the most popular type of fish or shellfish in the United States. (The other top species, in descending order of popularity, are salmon, Pollack, catfish, tilapia, crab, cod, clams and flatfish.) Many people also love to eat canned mackerel and salmon. Canned fish has long been considered one of the healthiest food choices. We eat it in sandwiches, on salads and, sometimes, just straight out of the can.

How healthy are canned fish in terms of their contents of long chain omega-3 (such as eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and long chain omega-6 fatty acids (such as arachidonic acid [AA])? Are there differences between "light" tuna and "white/albacore" tuna? Does it matter if the fish are canned in water or oil? Finally, do some canned fish contain more mercury than others?

To answer these questions, researchers from Purdue University studied 240 store-bought cans of fish. They analyzed four types of canned tuna: light tuna in water, light tuna in oil, white/albacore tuna in water and white/albacore tuna in oil. They also analyzed canned salmon and mackerel.

Their findings were published in late 2004 in The Journal of Food Science. (1) If you're a fan of light tuna, the results of this study are discouraging. Compared to other types of canned fish, light tuna canned in water or oil contains very little beneficial EPA. In some cases, light tuna canned in water actually contains less EPA than AA, which is the reverse of what you want. Interestingly, light tuna canned in oil contained less AA.

White/albacore tuna canned in water contains significantly more EPA than canned light tuna, up to 10 times as much. And the EPA to AA ratio is much more favorable, about four to one. But white/albacore tuna canned in oil contains as little EPA as most light tuna, with a poor EPA to AA ratio.

The study found that from a fatty acid prospective, canned salmon is more beneficial than any tuna product. It contains up to 29 times as much EPA as canned light tuna and up to five times as much EPA as white/albacore tuna canned in water. The EPA to AA ratio of canned salmon is up to 25 to one. Canned mackerel is almost as beneficial as canned salmon. Although it contains less EPA, the ratio of EPA to AA is about ten to one.

The Purdue University researchers also analyzed the mercury content of canned fish. The good news is that no canned fish exceeded the U.S. Food and Drug Administration's Action level of 1,000 parts per billion. But there were significant variations between the types of canned fish.

The researchers found that mercury levels in light tuna canned in vegetable oil were three times higher than those found in light tuna canned in water. They also found that light tuna in soy oil contained significantly higher amounts of mercury than light tuna canned in either water or vegetable oil.

White/albacore tuna canned in either water or soy oil had about the same or slightly higher amounts of mercury as light tuna canned vegetable or soy oil.

Compared to all canned tuna products, canned salmon and mackerel water had considerably lower levels of mercury, in some cases up to 17 times lower.

Despite the fact that canned white/albacore tuna contains considerably higher amounts of EPA than other tuna products, the researchers were concerned that its mercury levels were four times higher than those found in light tuna in water, salmon and mackerel.

Thus, canned fish including salmon and mackerel, provides the best of both worlds, low mercury and high EPA content. Consequently, these data suggest that these are the best options for those that frequently consume canned fish, and these canned fish are wonderful sources of EPA plus DHA that can easily be added to our diets. (2)

Literature cited.

Shim SM. Mercury and fatty acids in canned tuna, salmon and mackerel. Journal of Food Science 2004 69 (9). Published on Web 10/28/2004.

U.S. Department of Health and Human Services and U.S. Environmental Protection Agency. What you need to know about mercury in fish and shellfish: 2004 EPA and FDA advice for: Women who might become pregnant, women who are pregnant, nursing mothers, young children. March 2004.

A Large Study of Anti-Inflammatory Dietary Supplements Showed Positive Effects

an analysis by Ski Chilton, Ph.D.

Osteoarthritis is a huge problem that affects more than 50 million people in the United States alone. In early 2006, the National Institutes of Health released the results of the phase-three Glucosamine/chondroitin Arthritis Intervention Trial (GAIT), which tested the efficacy and safety of the dietary supplements glucosamine and chondroitin sulfate, alone and in combination, for the treatment of knee osteoarthritis. (1) The results were published in the New England Journal of Medicine in February 2006.

During the study, researchers randomly assigned 1,583 patients with knee osteoarthritis to receive 24 weeks of treatment with glucosamine, chondroitin sulfate, glucosamine and chondroitin sulfate in combination, Celebrex ï¿½ or placebo.

The researchers found that the combination of glucosamine and chondroitin sulfate was more effective than Celebrex ï¿½ at relieving moderate-to-severe knee pain and caused no significant adverse effects. Compared to the placebo group, the response rate in the glucosamine/chondroitin combination group was 24.9 percent higher while the response rate in the Celebrex ï¿½ group was 15.1 percent higher. (1)

It wasn't a complete victory for glucosamine and chondroitin sulfate. The study also found that these dietary supplements, either alone or in combination, were ineffective at relieving mild knee pain. There's no conclusive evidence that the supplements are effective in treating inflammatory conditions other than moderate-to-severe knee pain.

Still, the GAIT results are highly significant. Natural products usually don't get studied in a large-scale, phase-three clinical trial. When they do, the results have often been disappointing.

Literature cited.
1. Clegg DO. Glucosamine, Chondroitin Sulfate, and the Two in Combination for Painful Knee Osteoarthritis. NEJM 2006 ;354;795-808.

About What We Do & Our Goals

Within the next two decades, more than one in three US citizens will suffer from an inflammatory disease such as asthma, arthritis, diabetes, lupus, hay fever, Crohn's disease, eczema and heart disease. For example, more than 20 million Americans have asthma today -- twice as many as in 1980. These disturbing trends have created a new generation of sufferers who are seeking new ways to manage their debilitating diseases. The use of complementary/alternative medicine has dramatically increased in the developed world and especially in Western countries such as the United States. It is estimated that as much as 60% of the U.S. population has used or currently uses complementary/alternative medicine, spending in excess of $50 billion annually. Soy proteins, oat, bran, and psyllium have continued to be the largest-selling compounds, and there are increasing uses in fortified foods and beverages. However, polyunsaturated fatty acids have emerged as the leading group of functional additives expanding 30% annually through 2004.

The Center for Botanical Lipids brings together a group of outstanding investigators in three internationally recognized lipid groups to study the effects of dietary polyunsaturated fatty acids on human diseases that are driven by inflammation. Specifically, the lipid research groups in atherosclerosis and inflammation represent two well-established areas of research focus at Wake Forest University School of Medicine. Similarly, the lipid group at Brigham and Women's Hospital, a teaching affiliate of Harvard Medical School has been at the forefront in the area of lipid mediators of inflammation.

It is the Center's goal to carry out state of the art research in the area of botanical dietary fatty acids and human disease as well as to be an important resource for those who are interested in learning more about dietary fatty acids and those who are involved in research in this important area. We are very grateful to the National Institutes of Health and in particular the National Center for Complementary and Alternative Medicine and the Office of Dietary Supplements, for their generous support of our Center. We hope you will enjoy our site.

Annual Symposium on The Role of Dietary Fatty Acids in the Prevention and Treatment of Chronic Disea

October 24th

Center for Botanical Lipids hosted the First Annual Symposium on The Role of Dietary Fatty Acids in the Prevention and Treatment of Chronic Diseases held at Wake Forest University School of Medicine (read more... ).

Project 1: Mechanisms of Atherosclerosis Prevention by Flaxseed Oil

Project Leader: Lawrence Rudel, Ph.D.
Floyd (Ski) H. Chilton, III, Ph.D., Co-Investigator
John S. Parks, Ph.D., Co-Investigator
Iris Edwards, Ph.D. - Co-Investigator

Project 1 is designed to investigate the hypothesis that seed oil from flax (Linum usitatissium) provides effective protection against the development of atherosclerosis through its effects on plasma lipoprotein compositions and concentrations and on inflammatory responses of macrophages. Flaxseed oil as a food supplement is widely believed to have beneficial effects on coronary heart disease (CHD) in human populations although a comprehensive review of the pertinent literature on this subject in 2003 found only suggestive evidence of protection and indicated that more definitive work is needed to help understand the nature of any protective effect.

In preliminary studies in this laboratory, we have seen that dietary flaxseed oil reduced the extent of aortic atherosclerosis in genetically engineered mice. The goal of project 1 is to elucidate specific mechanisms that mediate such effects so that we may investigate their applicability in humans. We hypothesized that beneficial effects of flaxseed oil occur at least partly through the ?-linolenic acid (ALA)-induced alterations of hepatic lipid metabolism leading to a less atherogenic plasma lipoprotein profile. Additionally, we speculated that changes in fatty acid composition in cellular phospholipids due to ALA enrichment of precursor pools of fatty acids may lead to a reduction in inflammatory responses of macrophages in the artery wall. Accordingly, we have begun characterizations of the atherogenic responses to dietary flaxseed oil-induced modifications of plasma lipoprotein composition and metabolism. The B100+/+LDLr-/- mouse was chosen as the model because of its similarity in plasma lipoprotein profile to that seen in human beings. The principal cholesterol-carrying lipoprotein in the plasma of this animal is LDL containing apoB100, which is the primary candidate as the bad guy or promoter of atherosclerosis in human CHD patients. We are proposing to completely analyze the chemical composition of these lipoproteins, including the proportions and fatty acid makeup of each of the major lipid classes. We are proposing to examine the role of flaxseed oil in modifications of hepatic cholesterol metabolism that function in determination of the atherogenic changes in plasma LDL composition. Finally, we are proposing studies of the flaxseed oil-induced changes in inflammatory responses proliferated by macrophages as they may contribute to atherogenesis in this animal model.

All of the proposed endpoints are candidate mechanisms suspected of participating in the development of coronary heart disease in human patients, and the long term goal of such studies is to define the relevance of these findings to coronary heart disease prevention. The use of a relevant animal model to do invasive studies defining the molecular mechanisms involved in development of atherosclerosis should shorten the time required for installation of measures appropriate for prevention of CHD in human populations, consistent with the long term goal for this project which is prevention of CHD.

Project 2- Echium oil, triglyceride metabolism, and atherosclerosis

Project Leader: John S. Parks, PhD
Perry L. Colvin, M.D., Co-Investigator
Floyd (Ski) H. Chilton, Ph.D., Co-Investigator
Ji-Young Lee, Ph.D., Co-Investigator
Lawrence L. Rudel, Ph.D., Co-Investigator
Amanda Wibley - predoctoral student
Lolita Forrest - predoctoral student

Cardiovascular disease (CVD) is the leading cause of death in the United States and other Westernized societies. Consumption of fish oil (FO) or n-3 polyunsaturated fatty acid (PUFA) supplements has been shown to reduce the extent of atherosclerosis (i.e., hardening of the arteries), coronary heart disease (CHD), and stroke in epidemiological studies, in clinical trials, and in animal studies. The cardioprotective benefits of fish oil have been largely attributed to two n-3 fatty acids, eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3), whose enrichment in cells and plasma lipoproteins results in decreased inflammation, thrombosis, blood pressure, arrhythmias, endothelial activation, and plasma triglyceride (TG) concentrations.

In spite of the beneficial effects of FO, the consumption of n-3 fatty acids in the North American population is low. Consumption of vegetable oils containing -linolenic acid (ALA, 18:3 n-3) has only limited impact on tissue concentrations of EPA and DHA, since the conversion of 18:3 n-3 to EPA (20:5 n-3) is limited by the inefficiency of the -6 desaturase-catalyzed step. One strategy to enrich tissues in 20 and 22-carbon PUFAs is to use botanical oils that are enriched in fatty acids that bypass the -6 desaturase step of fatty acid elongation and desaturation. Echium oil, derived from the seeds of Echium Plantagineum, is enriched in stearidonic acid (SDA; 18:4 n-3), which is the immediate product of -6 desaturation of 18:3 n-3. Our preliminary clinical trials in mild to moderate hypertriglyceridemic human subjects have demonstrated that fatty acids in echium oil, presumably SDA, are metabolized to EPA and result in lower plasma TG concentrations that are similar to those observed with FO consumption.

The goals of this project are to determine the mechanisms by which echium oil reduces plasma TG concentrations and to determine whether echium oil supplementation will retard the development of atherosclerosis. Our hypothesis is that echium oil supplementation decreases plasma TG concentrations by decreasing hepatic TG synthesis and secretion and by increasing the catabolism of plasma TG-enriched lipoproteins. In addition, we hypothesize that echium oil supplementation will reduce atherosclerosis to an extent similar to that observed with FO supplementation, by decreasing the production of inflammatory mediators and through plasma lipoprotein lowing. We will test our hypothesis using a moderately hypertriglyceridemic animal model, the apoB100 only-LDL receptor knockout (B100-LDLrKO) mouse that responds to FO with a significant decrease in plasma TG concentrations and very low density lipoprotein (VLDL) cholesterol concentrations, without a significant decrease in low density lipoprotein (LDL) or high density lipoprotein (HDL) cholesterol, compared to saturated (sat’d) fat fed controls.

In specific aim 1, we hypothesize that echium oil supplementation will reduce plasma TG concentrations to a degree similar to that observed with fish oil supplementation in B100-LDLrKO mice. Mice will be fed atherogenic diets containing 10% calories as palm oil, 0.2% cholesterol, and supplemented with increasing amounts of palm oil (control), echium oil, or fish oil (control) up to 20% of total calories as fat. After eight weeks of diet consumption, mice will be bled for quantification of plasma lipids, and whole plasma and liver cholesteryl ester (CE), phospholipid (PL), and TG fatty acid compositions. On the basis of results in this specific aim, we will use an amount of echium oil supplementation that results in a 30-40% decrease in plasma TG concentrations relative to palm oil for specific aims 2-4.

In specific aim 2, we will test the hypothesis that echium oil supplementation decreases plasma TG concentrations by down regulation of genes involved in hepatic TG synthesis, resulting in less hepatic TG synthesis and reduced VLDL TG, but not apoB, secretion. Using the experimental groups outlined in specific aim 1, the following will be determined:

plasma lipid and lipoprotein concentrations, and chemical and fatty acid compositions of plasma lipoproteins,
hepatic perfusate VLDL TG and apoB100 accumulation during recirculating liver perfusion and hepatic perfusate VLDL TG and apoB synthesis during non-recirculating liver perfusion,
hepatic mRNA abundance of genes involved in hepatic TG synthesis and sterol regulation.

specific aim 3

postprandial TG response to the supplemented oils during atherogenic diet consumption,
post heparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities with a standard TG substrate preparation,
rate of lipolysis of postprandial TG enriched particles by purified LPL in vitro,
rate of endogenous lipolysis after intravenous heparin injection and oral supplement oil load,
in vivo catabolism of plasma VLDL particles.

specific aim 4

atherosclerosis extent by measuring aortic free (FC) and esterified cholesterol (EC) content,
aortic mRNA abundance for genes involved in endothelial activation and inflammation,
production of inflammatory mediators by elicited macrophages that have been activated in vitro with oxidized LDL (oxLDL) or lipopolysaccharide (LPS).

Project 3- Mechanism of Leukotriene Inhibition by a Borage Seed Oil Emulsion

Project Leader: Floyd (Ski) Chilton, Ph.D.
Scott Hemby, Ph.D., Co-Investigator
Jonathan A. Arm, M.D., Co-Investigator
Priscilla Ivester - Research Coordinator
Kelly Weaver - predoctoral student

Objective
We and others have demonstrated that dietary fatty acids such as gammalinolenic acid (GLA) eicosapentaenoic acid (EPA) and stearidonic acid (SDA), which are available over-the-counter in dietary supplements, inhibit the production of mediators of inflammation including leukotriene generation, a proven approach to the management of asthma. The overall objective of project 3 of the Center Grant is to conduct systematic studies to evaluate the molecular mechanism by which these supplements inhibit inflammation. It is our hypothesis that the levels of circulating fatty acids control the quantity of inflammatory messengers produced within inflammatory cells that participate in inflammatory diseases. We believe a better understanding of how these supplements work will facilitate the development of more effective fatty acid-based therapies that inhibit inflammatory diseases in humans.

Specific Aims
A family of inflammatory messengers, known as leukotrienes, has been shown to contribute to the pathogenesis of several inflammatory diseases. The major goal of specific aim 1 is to elucidate in humans the mechanism by which dietary fatty acids found in borage and marine oil combinations inhibit inflammatory mediator production in general and leukotriene generation in particular. Initial studies are designed to determine the biochemical basis by which dietary fatty acids block leukotriene production. Additionally, our clinical trials in both asthmatic and control subjects suggest that dietary fatty acid manipulation potently blocks leukotriene production in some subjects but not in others. More specifically, those subjects that produce high levels of leukotrienes are the subjects that responded best to dietary fatty acid manipulation. Studies in the second part of specific aim 1 are focused at understanding the genetic basis why some individuals respond to dietary fatty acid and others do not.

In the near future, newly developed seed oils from plants such as Echium Plantagineum are likely to be the basis for a number of important therapeutic products. Studies in specific aim 2 are designed to determine whether this seed oil (containing stearidonic acid and GLA) can influence inflammatory mediator production including leukotriene generation in human subjects. Our preliminary data demonstrate that echium oil, provided to humans, markedly reduces serum triglycerides in hyper-triglyceridemic patients without adversely affecting circulating arachidonic acid levels (J. Nutrition, 2004 134: 1406-1411). These studies raise critical questions of whether this promising botanical oil can inhibit the production of inflammatory mediators including leukotrienes in humans and thereby be developed as an anti-inflammatory therapeutic.

Project 4- Treatment of Bronchial Asthma with Borage Seed Oil

Project Leader: Jonatham Arm, M.D.
Elliot Israel, M.D. - Co-Investigator
Lin Wang - Laboratory Technician

Asthma affects ~20 million Americans and results in annual direct and indirect health care costs of ~$8 billion. Despite substantial improvements in our understanding of the epidemiology and pathobiology of asthma, its incidence has doubled in the last decade. Morbidity and mortality from the disease has risen proportionally and is especially prevalent among minority individuals.

There is a substantial body of evidence implicating a group of lipid mediators called leukotrienes in the pathogenesis of asthma. Leukotriene modifying drugs are now an established treatment for the disease. These drugs fall into two categories; those that inhibit the generation of leukotrienes through inhibition of the enzyme, 5-lipoxygenase (5-LO), and those that antagonize the actions of the cysteinyl leukotrienes (Cys-LTs) at the type 1 receptor (CysLT1R). Development of 5-lipoxygenase inhibitors was hampered by liver toxicity. The only drug to enter the market, Zileuton®, requires administration 4 times a day (leading to problems with compliance) and causes significant liver inflammation in ~4% of individuals. While there are no studies that have directly compared the efficacy of 5-LO inhibitors with CysLT1R antagonists in the management of asthma, analysis of the available data suggest that 5-LO inhibition is the more effective approach. Therefore, the availability of an effective, non-toxic, inhibitor of 5-LO that can be administered once or twice a day would be immensely beneficial.

Borage seed is rich in gamma linolenic acid (GLA). Dietary supplementation with borage seed oil provides non-toxic effective inhibition of leukotriene generation. Mechamism-based studies suggest that these supplements have their effects by blocking 5-LO. However, GLA also adversely increases circulating free arachidonic acid (AA), which has pro-inflammatory potential. Supplementation of borage seed oil with the n-3 fatty acid, eicosapentaenoic acid (EPA), derived from fish-oil, prevents the conversion of GLA to AA by
5-desaturase, thereby preventing increases in circulating AA. While EPA is an effective inhibitor of 5-desaturase, it is extracted from fish oil and is not well-tolerated due to its taste, smell and mouth-feel properties. Furthermore, higher doses of EPA appear to blunt the effect of GLA as an inhibitor of leukotriene biosynthesis. Stearidonic acid (SDA), is a metabolic precursor of EPA that is extracted from seed oils of botanical sources such as Echium Plantagineum. Importantly, out laboratory has shown that humans convert this oil to EPA and yet it does not have the organoleptic properties of EPA. This raises the exciting possibility that stearidonic acid in botanical oils may be a vegetable alternative for fish oil. To test this hypothesis, we will;

Determine the optimal dose of SDA, in echium seed oil, that inhibits the rise in serum arachidonic acid when combined with GLA while maintaining effective inhibition of leukotriene generation in asthmatic individuals, and

Determine the efficacy of the optimal combination of GLA and SDA on the severity of mild to moderate persistent asthma.

Regulation of Inflammation and Innate Immunity by Phospholipase A2

October 18th

Jonathan Arm, MD, Associate Professor of Medicine, Brigham and Women's Hospital, Division of Rheumatology, Immunology and Allergy, and PI of CBL Project 4 presented "Regulation of Inflammation and Innate Immunity by Phospholipase A2" to Division of Pulmonary, Critical Care, Allergy and Immunologic Diseases at Wake Forest University School of Medicine.

Pilot Project Grants Deadline

October 16th

Deadline for submission of Pilot Project Grants.

ACAT2 - The Source of Atherogenic Cholesteryl Esters

October 4&6th

Larry Rudel, PhD, presented "Why Monounsaturated Fat Offers Little Protection Against Atherosclerosis" and "ACAT2 - The Source of Atherogenic Cholesteryl Esters" at The Australian Atherosclerosis Society Annual Scientific Meeting, Couran Cove, Queensland, Australia.

The Role of ACAT2 in LDL Composition and Atherosclerosis

October 3rd

Larry Rudel, PhD, presented "The Role of ACAT2 in LDL Composition and Atherosclerosis" at the University of Queensland, Brisbane, Australia.

Use of mouse molecular genetics to understand the pathogenesis of Tangier disease

September 27th

John Parks, PhD, presented "Use of mouse molecular genetics to understand the pathogenesis of Tangier disease" to the North Carolina Central University, Julius L. Chambers Biomedical/Biotechnology Research Institute, Durham, NC.

The Role of Liver ABCA1 Transporter in Determining Tangier Disease Lipid Phenotype

September 20th

John Parks, PhD, presented "The Role of Liver ABCA1 Transporter in Determining Tangier Disease Lipid Phenotype" as the General Clinical Research Center Seminar, Wake Forest University Health Sciences, Winston-Salem, NC.

The role of dietary fatty acids in the prevention and treatment of inflammatory disease

September 18th

Floyd (Ski) Chilton, PhD, Professor of Pharmacology and Physiology at Wake Forest University School of Medicine, Director of the Center for Botanical Lipids, and PI of CBL Project 3 presented "The role of dietary fatty acids in the prevention and treatment of inflammatory disease" to the Department of Nutrition at the University of North Carolina at Greensboro.

The Central Role of ACAT2 in Atherosclerosis

September 13th

Larry Rudel, PhD, presented "The Central Role of ACAT2 in Atherosclerosis" to the Department of Science and Pharmacology, Universita Degli Studi Di Milano, Italy

Monounsaturated Fats Do Not Protect Against Atherosclerosis: A Molecular Explanation

September 11th

Larry Rudel, PhD, presented "Monounsaturated Fats Do Not Protect Against Atherosclerosis: A Molecular Explanation" at the University of Bologna, Bologna, Italy.

CLA activates cell signals that cause human adipocyte delipidation” to the CBL monthly seminar

September 4th

Larry Rudel, PhD, Professor of Pathology/Lipid Sciences, PI of Project 1 presented "Michael K. McIntosh, PhD, RD, the L.S. Keker Excellence Professor from the Department of Nutrition at UNC-Greensboro, presented "CLA activates cell signals that cause human adipocyte delipidation" to the CBL monthly seminar." to State of the Art Lecture at The European Lipoprotein Club 29th Annual Meeting, Tutzig, Germany

CLA activates cell signals that cause human adipocyte delipidation

August 17th

Michael K. McIntosh, PhD, RD, the L.S. Keker Excellence Professor from the Department of Nutrition at UNC-Greensboro, presented "CLA activates cell signals that cause human adipocyte delipidation" to the CBL monthly seminar.

Analysis of macrophage-specific Abca1 knockout mice

July 2-7

John Parks, PhD, Professor of Pathology/Lipid Sciences, PI of Project 2 presented "Analysis of macrophage-specific Abca1 knockout mice" as an invited Speaker and Session Chair at the Lipoprotein Gordon Conference, Mount Holyoke College, South Hadley, MA.

Floyd “Ski” Chilton, PhD

Lawrence L. Rudel, Ph.D.

John Parks, Ph.D.

James T. Stevens, Ph.D.

Natural Living

38.2 million American adults (about 19 percent) use nonvitamin, nonmineral natural products, primarily botanical supplements.

Diabetic Epidemic

More than 18 million people have diabetes, with 1.3 million newly diagnosed each year.

Inflammation Epidemic

More than one in three US Citizens will suffer from an inflammatory disease.

Our Children’s Health

Asthma deaths among children have increased 4%.

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