- Email: [email protected]
Report on ISSFAL 2012
Prostaglandins, Leukotrienes and Essential Fatty Acids 87 (2012) 53–56
Contents lists available at SciVerse ScienceDirect
Prostaglandins, Leukotrienes and Essential Fatty Acids journal homepage: www.elsevier.com/locate/plefa
ISSFAL Society Section
Report on ISSFAL 2012 Francesco Visioli IMDEA-Food, Madrid, Spain
The 2012 ISSFAL meeting took place in beautiful Vancouver from May 26 to May 30, 2012 and was hosted by Drs. Tom Clandinin, Sheila M. Innis, and Catherine J. Field. More than 500 delegates attended the sessions and contributed with posters and oral presentations. A notable aspect of ISSFAL meetings is the lively, informal, and friendly atmosphere, which facilitates discussion and interaction among participants and creates optimal ground for new collaborations and friendship. PLEFA readers who could not attend ISSFAL 2012 will here find a summary of the sessions. Please note that this report will obviously be biased in that, not being ubiquitous, I could not attend all parallel sessions and I have professional preferences. However, an entire issue of PLEFA will soon feature plenary lectures, so that interested readers will have an opportunity to deepen their knowledge and have an updated picture of fatty acids and lipids research. The meeting started with a breakfast workshop on ‘‘Hearth Healthy Diet’’, which was well-attended and featured brief presentations by Drs. Peter Zock, Peter Jones, Cyril Kendall, and Penny Kris-Etherthon. Emphasis was placed on the need to prefer low-glycemic index foods and the possibility to supplement diets with phytosterols in cases of hypercholesterolemia. Further, small dietary modifications have great potential to contribute to lowering plasma cholesterol and should be promoted by physicians and opinion leaders. Two parallel Plenary Sessions kicked off the scientific program. The recent (2010) winner of the ISSFAL Early Career Award, Dr. John Paul SanGiovanni lectured on ‘‘DHA and retinal function’’, stressing attention on DHA and its 5-lipoxygenase metabolite 4-HDHA, which mediates the anti-angiogenic effects of DHA. Strong biochemical data do indeed link low DHA retinal concentrations with degeneration and onset of vision disorders. This is especially important for the elderly and preventive strategies now rely on solid evidence. This notion was reinforced by one of the subsequent concurrent symposia, in which Drs. Yves Sauve´ and Martin-Paul Agbaga further reviewed our current knowledge on the roles of long chain omega 3 fatty acids and PUFAs in retinal function and degeneration. The overall conclusion (which echoes what was said by Dr. Gene Anderson at the Brighton ISSFAL meeting) is that we still have much to investigate to obtain a clear view of the precise roles of PUFAs in the retina. In particular, while there is extensive evidence that insufficient DHA intakes and/or altered retinal metabolism are strongly associated with
E-mail address: [email protected] 0952-3278/$ - see front matter http://dx.doi.org/10.1016/j.plefa.2012.07.001
macular degeneration, provision of omega 3 fatty acids did not prove to be a viable therapeutic option. Therefore, we need better understanding of transport systems and of the potential use of supplements to slow down or even revert retinal degeneration. The evergreen theme of saturated fats and cardiovascular health was discussed in one of the four parallel symposia that followed the first coffee break. Dr. Bob Gibson gave an interesting initial overview, using a fresh approach to the issue and trying to underscore the various confounders that undermine all epidemiological studies of saturated fats and health. The topic was subsequently expanded by Dr. Kim Jackson, who pointed to the fact that genetics plays a major role in individual response to dietary manipulation (in this case, with saturates). As an example, E4 are particularly sensitive to interventions with different fatty acids: the SatGene study is, in fact, designed to assess the impact of altered fat content and composition on the blood lipid profile according to the APOE genotype. Therefore, without knowing the individual genetic background, it appears difficult to propose general rules on the exact proportion of saturates that should make part of an optimal diet. Dr. Brian Rodrigues presented a series of very interesting studies on lipoprotein lipase(s), which are paramount in providing essential fuel to the heart. These enzymes are often being attributed with noxious properties and our knowledge of them appears to be rather limited. In diabetes, absolute or relative lack of insulin impairs cardiac glucose transport and oxidation, resulting in fatty acids becoming the preferred means of energy supply. This, in turn, starts a vicious cycle in which lipoprotein lipases become upregulated resulting in abnormal fatty acid supply and utilization by the heart tissue that could potentially initiate and sustain cardiac dysfunction. Therapeutic options are under scrutiny and might provide viable tools in the near future. Dr. Charles Serhan gave one of the two concurrent Plenary Lectures of Sunday afternoon. He extensively reviewed the multiple biological actions of resolvins, maresins, and protectins and presented new exciting data on their anti-microbial activities. Indeed, while the mechanisms of action are still to be elucidated and currently do not rest on biochemical hypotheses, the use of these fatty acid mediators allows decreasing the dose of antibiotics necessary to heal infected animals. Of course, these exciting data add to the plethora of interesting activities attributed to such lipid mediators. The conclusion that can be drawn is that resolution of acute inflammation is an active programmed process that also stimulates tissue regeneration. Provision of resolvins etc. basically speeds up the body’s natural reaction to inflammatory stimuli. Whether these compounds will ever enter into the pharmaceutical
54
ISSFAL Society News / Prostaglandins, Leukotrienes and Essential Fatty Acids 87 (2012) 53–56
realm is as yet to be proven, but – based on the available data – we can certainly envision the future use of EPA- and DHA-derived resolvins, maresins, and protectins as medicine. The controversy of whether omega 3 fatty acids exert antiarrhythmic activities has been addressed by Dr. Rozenn Lemaitre, who opened a parallel symposium on ‘‘Fatty Acids and Preventive Medicine’’. As a matter of fact, after the first positive reports, subsequent studies did not confirm the anti-arrhythmic activities of omega 3. Differences among methods, patient selection, individual needs and genetics might account for these discrepancies. As of today, we cannot really conclude that omega 3 fatty acids are anti-arrhythmic and further studies are necessary. In the same symposium, Dr. Kevin Maki reviewed the evidence linking hypertriglyceridemia to cardiovascular disease. As of today, no large-scale, prospective outcomes trial has been completed to evaluate the efficacy of lipid-altering drug therapy in patients specifically selected for the presence of hypertriglyceridemia. The best we can do is to extrapolate results from trials with statins, fibrates, and omega 3 fatty acids aimed at other patients. Interestingly, non-HDL cholesterol appears to be a better predictor of CV disease than LDL-cholesterol (see SM Boekholdt JAMA 2012). Therefore, ad-hoc trials are warranted and, in this respect, specific fatty acids might play interesting therapeutic roles. Interested readers might want to check a recent Mozaffarian review (J Nutr 2012) on the different effects of DHA and EPA (if there are any, as he concludes). Monday morning started with another Breakfast Workshop, which was sold out and I didn’t attend. This, however, tells us about the urgent need to ameliorate and standardize fatty acid analyses (see later under ISSFAL Membership Meeting). The second day of the meeting started with two concurrent plenary lectures. I attended the one given by Dr. James Ntambi, who reviewed the effects of fatty acids on gene expression and its regulation. In particular, his group is using the stearoyl-CoA desaturase (SCD) mouse model to investigate the role of de novo synthesized fatty acids in the regulation of lipogenic gene expression. In his lecture, Dr. Ntambi proposed hepatic MUFA as regulators of lipogenesis and gluconeogenesis, with oleate being more potent than palmitoleate. In a way this might in part explain the high incidence of obesity in high-MUFA consumers. Four parallel symposia followed. The one on Fatty Acids and Metabolic Regulation was chaired and opened by Dr. Jan Kopecky, who presented an overview of the role of omega 3 fatty acids in the treatment of the metabolic syndrome. His conclusions were that we still don’t know much about the exact role that omega 3 fatty acids might play in the development and/or the treatment of the metabolic syndrome. As an example, the relation of omega 3 with obesity is still not clear, even though these fatty acids decrease cell proliferation. In addition, omega 3 fail to improve glycaemic control in diabetic patients. In brief, omega 3 per se appear to be ineffective in the treatment of the metabolic syndrome. However, they might prove useful as adjunct treatment, for example by adding omega 3 to mild calorie restriction, which efficiently reduces body fat accumulation, while inducing a metabolic switch toward lipid catabolism in adipose tissue. Other mixed data were shown by the subsequent speakers. In particular, Dr. Anna de Boer showed how omega 3 decrease proinflammatory adipokine secretion in an interesting co-culture model of adipocytes and macrophages, hinting at anti-inflammatory effects. Dr. Michel Narce compared the effects of omega 3 (from linseed oil) and omega 6 (from sunflower oil) in livers of Zucker rats (a model of metabolic syndrome). While steatosis was decreased by the former, it was conversely increased by the latter, suggesting differential modulation of lipid liver biosynthesis and insulin sensitivity in the early state of metabolic syndrome. This presentation followed that of Dr. Darshan Kelley, who tested the effects of DHA supplementation
(3 g/d, 90 d) in the absence of EPA on glucocentric and lipocentric markers of insulin resistance in hypertriglyceridemic men. No dramatic functional effect was noted and the conclusion was that further studies are required to elucidate (or rule out) the role of DHA and omega 3 in this kind of patients. [contributed by Dr. Nathalie Nicod] The session on ‘‘Interesterified and novel fatty acid sources’’ was opened by Dr. Kalyana Sundram who gave a valuable overview on the nutritional outcomes of the interesterification of fats. Dr. Thomas Sanders followed by showing a study in which interesterifaction of palm oil had no adverse effects on cardiovascular risk factors. Fatty acid ethanolamides were introduced by Dr. Lin Lin, who showed that they associate with energy metabolism in humans. Dr. Sebastiano Banni followed by showing that a endocannabinoid balance between visceral and subcutaneous adipose tissues is crucial for body fat homeostasis and low doses of dietary n-3PC are able to significantly improve metabolic syndrome in obese Zucker rats. Aside from plenary lectures, one of the most attended sessions was the one on linoleic acid, which underscores the interest of the scientific community (namely, lipidologists) for this issue. Over the past few years, a heated though professional debate is developing over the health effects of omega 6 vs. omega 3 fatty acids. While some researchers claim that omega 6 fatty acids actually increase cardiovascular risk (notably via inflammatory actions), others argue the exact opposite, i.e. that omega 6 fatty acids decrease blood cholesterol and, hence, cardiovascular risk and mortality. The truth is that there are very few well-conducted randomized trials and that we often base our discussion on surrogate markers. This symposium – aptly named Linoleic Acid: Roles in Human Health and Requirements – addressed this hot topic with three highly-qualified scientists. The first one, Dr. Joe Hibbeln, formulated the hypothesis that endocannabinoids and their receptors can be modulated by linoleic acid and, therefore, lead to dissatisfaction, hunger, increased needs to be satisfied, and, in turn, increased obesity. Indeed, soybean oil (one of the two most popular oils worldwide) is the only food item associated with increased obesity. This challenging view pairs with the increased levels of consumption of linoleic acid witnessed in the Western world over the past decades. Moreover, alpha-linolenic acid consumption in the East is associated with decreased cardiovascular mortality, whereas linoleic acid consumption is not. According to Dr. Hibbeln, linoleic acid increases cardiovascular risk, as indicated by several striking correlation between intakes and epidemiology. To gain mechanistic insights over the potentially noxious effects of linoleic acids and omega 6, Dr. Kevin Fritsche reviewed randomized controlled trials that permitted the assessment of dietary linoleic acid on biological markers of chronic inflammation. Fifteen studies (eight parallel and seven cross-over) met inclusion criteria. None of the studies reported significant findings for a wide variety of inflammatory markers including C-reactive protein, fibrinogen, plasminogen activator inhibitor type 1, cytokines, soluble vascular adhesion molecules or tissue necrosis factor-alpha. Therefore, as of 2012, there is no evidence from randomized, controlled intervention studies among healthy, noninfant humans to show that variations in the level of linoleic acid in the diet affect in vivo inflammation in healthy humans. It is noteworthy that most trials include small numbers of participants, are of short duration, and usually do not report on alpha-linolenic acid intakes. Given that linoleic acid intake lowers plasma cholesterol, its putative negative effects on cardiovascular mortality are puzzling. To further fuel the debate, Dr. Christopher Ramsden re-analyzed data from the Sydney Heart Trial, a secondary prevention trial that selectively tested safflower oil without confounders such as short chain omega 3 fatty acids. The results show that this treatment increased all-cause and cardiovascular mortality. Inclusion of these data to a meta-analysis of the effects of fatty acids on mortality leads to the conclusion that provision of linoleic acid
ISSFAL Society News / Prostaglandins, Leukotrienes and Essential Fatty Acids 87 (2012) 53–56
non-significantly increases overall mortality in all trials and significantly increases mortality in secondary prevention trials. There are numerous caveats to be taken into account: these trials adopted high doses of PUFAs, often included few subjects, do not account for unknown confounders, and might not apply to the general population. The overall conclusions of Dr. Ramsden were that the term ‘‘PUFA’’ means very little in terms of human health, that we should stress that health benefits are conveyed by EPA and DHA, that – in vivo – it is difficult to disentangle the individual effects of linoleic and alpha-linolenic acid (normally both present in vegetable oils), and that there are no proven benefits of the former, which might actually increase mortality rate. Of course, as I mentioned earlier, this is a highly-debated topic that does indeed require more investigation (however costly and difficult to perform). Biochemical bases are also strong in theory, but weak in practice, confounders are difficult to eliminate, and sometimes individual bias and ideas lead to misinterpretation. In short, do make an effort to attend future ISSFAL meetings to keep up with the latest news. During lunch break/poster session, Dr. Bob Gibson chaired a very interesting session devoted to a ‘‘three minute thesis competition’’. As the title suggests, selected students had a chance to present their work in a condensed way. This session was very well received, lively, and educational at the same time. The meeting resumed with the Alexander Leaf Award Lecture, given by the recipient Dr. Bob Gibson, who gave an historical overview of his studies on maternal nutrition, with particular focus – of course – on fatty acids. Mixing history, old photographs of him and his mentors and colleagues, biochemistry, clinical trials, failure and success, Dr. Gibson’s entertaining lecture was a clear example of how science and biomedical research progress. Younger attendees did certainly learn important lessons from this lecture. Of the two concurrent Plenary Sessions that followed, I chose that of Dr. Klaus Gawrisch, on membrane lipid–protein function. One of the things I learned is that membranes are so fluid they constantly move and fluctuate. Their packing into the classical bilayer puts them under tensile stress. Modulation of membrane fluidity by fatty acids heavily influences G protein-coupled membrane receptors (GPCR), which comprises receptors for dopamine, serotonin, epinephrine, opioids, cannabinoids, etc. These receptors can be reconstituted to study their modifications by individual fatty acids and predict – to a certain extent – how the cell would react to stimuli once we modify its lipid composition. Four parallel symposia followed. I managed to attend two of them (though not at the same time y). In the first one, Dr. Grant Pierce illustrated the Flax-PAD study, a large (though he calls it small) clinical study on the effects of flaxseed (rich in alphalinolenic acid) in patients with peripheral arterial disease. In this trial, bread and muffins added with linseed were provided to patients, who witnessed a decrease in blood cholesterol and a remarkable decrease in systolic and – to a slightly lower extent – diastolic blood pressure. The magnitude of this effect is stronger than that of other dietary interventions and is comparable with some anti-hypertension drugs. The effects of alpha-linolenic acid were also studied by the group of Dr. Lindsay Brown. In particular, they studied chia oil, of which Australia is the principal producer. Their results show that, in rats, chia oil improves cardiac and hepatic functions when animals are fed a high-fat, high-sugar diet to induce approximation of metabolic syndrome. In the adjacent room, our Editor in Chief Dr. Richard Bazinet outlined his studies on cerebral uptake of fatty acids. The most interesting findings are that the brain vary rapidly beta-oxidizes EPA (which might explain why its levels are so low) while maintaining a tight homeostasis of DHA. Indeed, it takes months
55
to replace cerebral DHA (which also shows selected incorporation into areas and phospholipids, as recently published by yours truly). These studies will help proper targeting of adjunct therapy with omega 3 fatty acids in neurological disorders. The final talk was given by Dr. Gunter Eckert, who treated aged mice (who have lower brain DHA levels) with long-chain omega 3 fatty acids and showed improved mitochondrial respiratory chain (especially complex IþII and IV activities) and ATP production. After the now traditional ‘‘Meet the Professors’’ breakfast, organized by Dr. Richard Bazinet, two plenary sessions opened the Tuesday section of the meeting. In one of them, Dr. Patrick Tso gave a very interesting, didactic, and entertaining lecture on how we digest and transport triacylglycerols. His lecture spanned from the roles of gastric lipase and pancreatic lipase to the mechanism of chylomicron formation in the enterocytes and the role of various apolipoproteins in intestinal lipid transport by the enterocytes. Answering several questions, Dr. Tso further illustrated the biochemical pathways involved in fat absorption (which is way more complex than I thought). [Contributed by Dr. Nathalie Nicod] A very interesting and diverse symposium was the ‘‘President’s hot topics session’’, in that it brought up-to-date insights to fatty acids and nutrition. Dr. Rinat Ran-Ressler started the session with a very interesting talk on the effect of branched chain fatty acids (BCFA) on necrotizing enterocolitis (NEC). BCFA are found in the normal term human newborn gut, deposited as major components of vernix caseosa and ingested during late fetal life. The researchers fed pups with 20% BCFA and found that NEC incidence was reduced by 56% and the composition of the microbiota was altered in the BCFA group compared to the control group. Dr. Adina Michael-Titus demonstrated that after thoracic compression, FAT-1 mice, which can synthesize DHA, display better functional locomotor recovery compared with the wildtype mice on a high omega-6 diet and WT mice on a normal diet. This improved neurological outcome was associated with a significant increase in neuronal and oligodendrocyte survival. Dr. Anne Marie Minihane showed an interesting association between genotype and diet. Her group found a greater sensitivity of plasma lipids and CRP to dietary fat quantity and composition, in APOE4 carriers (E3/E4), relative to E3/E3 genotype. Although both genotypes benefited from the TG lowering effects of DHA, E3/E4 individuals showed a more marked response, indicating additional hypotriglyceridaemic benefit in this large population subgroup. Thus, they suggest that the E4/E4 population might be even more responsive to diet. N-acyl-phosphatidylethanolamines (NAPEs) are normally synthesized in the small intestine and their metabolites increase satiety and decrease food intake. Dr. Sean Davies showed that mice fed a transformed Escherichia coli that catalyzes NAPE formation gained 29% less weight then controls with a decrease in body fat and not lean mass, due to a lower intake. These remarkable results suggest that manipulation of the microbiota may help treat obesity. Dr. Gregory Shearer ended the session by presenting the changes in specific lipoprotein oxylipins in Metabolic Syndrome, and concluded that omega-3 ethyl ester treatment corrects or hypercorrects these changes and thus oxylipins are likely to improve lipoprotein signaling. The ISSFAL Early Career Award was given to our Associate Editor Dr. S. Raza Shaikh, who is studying lipid rafts and the role of fatty acids in membrane physiology. One of his most interesting observations is that DHA, which greatly changes membrane’s properties, does incorporate into lipid rafts, although it does not do so easily because it does not bind cholesterol and because of steric incompatibility. However, once DHA is made part of the raft, it stabilizes it and creates more ordered structures.
56
ISSFAL Society News / Prostaglandins, Leukotrienes and Essential Fatty Acids 87 (2012) 53–56
Following the Early Career Award, another important ceremony took place, i.e. the New Investigator Award. Drs. Melissa Gregory, Zacharoula Nikolakopoulou, and Sarah Orr were given this important ISSFAL awards and were chosen among several outstanding young investigators who are developing their independent career. This award confirms ISSFAL’s mission to support investigators in the area of fatty acids and lipids and to create opportunities for young scientists to carry out high-quality research. One of the milestones of every ISSFAL conference is the Membership Meeting. This is a unique opportunity for ISSFAL members to meet with the Executives and propose ideas to further develop our society. In this occasion, some suggestions have been made to have a successful ISSFAL 2014 (in Stockholm). Examples included topics, organization of symposia, etc. One general question was asked about the use of PLEFA as our official journal. It needs to be remembered that PLEFA and ISSFAL interact in that building a strong journal largely depends on ISSFAL members. With a strong and widely-read official journal, ISSFAL will also grow further in status and membership. Therefore, members are encouraged to submit high-quality manuscripts to PLEFA and to cite PLEFA papers whenever possible. As a matter of fact, the 2011 Impact Factor is 3.4, i.e. it doubled as compared to the 2010 one, which is exactly the result of high-quality submissions and ever-increasing citations. Other issues concerned membership (on the rise) and financial status (solid). Finally, it was proposed to create a consensus over fatty acid analysis and come up with an ‘‘ISSFAL-endorsed’’ methodology that should be followed worldwide. We tried to do this before via the newsletter and the response was [euphemistically] less than enthusiastic. The idea, however, is worth pursuing so stay tuned for future developments. One innovative feature of ISSFAL 2012 was the participation of scientists/opinion leaders who work in areas collateral to our own
biomedical research. One notable example was that of Dr. Villy Christensen, who gave a rather worrisome overview of the fishing industry and the challenges we are facing to maintain our oceans healthy and full of fish. Apparently, quite the converse is happening: overfishing is stressing the aquatic environment and the future is not bright. Several initiatives are being taken: one of them is the Nereus Program (http://www.nereusprogram.org/ content/nereus-ocean-visualization), a think-tank which brings together several stakeholders to address the issue of over-exploitation of the world’s fish resources. Although immediate, clear actions are not being proposed, this international research and outreach network is focused on understanding the status of the global ocean and how we can ensure that there will continue to be seafood and a healthy ocean. We will certainly follow its future developments. One of the final two concurrent plenary sessions featured Dr. Parveen Yaqoob, who talked about fatty acids and immune function. Her conclusion was that fatty acids do influence immunity in different ways. The extent and precise nature of such influence is still unclear, especially in vivo. One example she illustrated is that of the FAT-1 mouse, which is protected from colitis, but experiences higher incidence of pulmonary tuberculosis. In humans, the picture is even more unclear and we need further investigation, especially in the elderly where the immune function is often compromised. In conclusion, ‘‘Well done!’’ to the organizers and the sponsors (which can be found in the ISSFAL 2012 website) for this flawless meeting which, as always, brought together the very best of lipid science, once again intermingling solid science with friendly exchange of projects and friendship. We will all see each other again in 2014 in Stockholm, where preparations by Dr. Brigitte Strandvick and her collaborators are already at an advanced stage.
Contents lists available at SciVerse ScienceDirect
Prostaglandins, Leukotrienes and Essential Fatty Acids journal homepage: www.elsevier.com/locate/plefa
ISSFAL Society Section
Report on ISSFAL 2012 Francesco Visioli IMDEA-Food, Madrid, Spain
The 2012 ISSFAL meeting took place in beautiful Vancouver from May 26 to May 30, 2012 and was hosted by Drs. Tom Clandinin, Sheila M. Innis, and Catherine J. Field. More than 500 delegates attended the sessions and contributed with posters and oral presentations. A notable aspect of ISSFAL meetings is the lively, informal, and friendly atmosphere, which facilitates discussion and interaction among participants and creates optimal ground for new collaborations and friendship. PLEFA readers who could not attend ISSFAL 2012 will here find a summary of the sessions. Please note that this report will obviously be biased in that, not being ubiquitous, I could not attend all parallel sessions and I have professional preferences. However, an entire issue of PLEFA will soon feature plenary lectures, so that interested readers will have an opportunity to deepen their knowledge and have an updated picture of fatty acids and lipids research. The meeting started with a breakfast workshop on ‘‘Hearth Healthy Diet’’, which was well-attended and featured brief presentations by Drs. Peter Zock, Peter Jones, Cyril Kendall, and Penny Kris-Etherthon. Emphasis was placed on the need to prefer low-glycemic index foods and the possibility to supplement diets with phytosterols in cases of hypercholesterolemia. Further, small dietary modifications have great potential to contribute to lowering plasma cholesterol and should be promoted by physicians and opinion leaders. Two parallel Plenary Sessions kicked off the scientific program. The recent (2010) winner of the ISSFAL Early Career Award, Dr. John Paul SanGiovanni lectured on ‘‘DHA and retinal function’’, stressing attention on DHA and its 5-lipoxygenase metabolite 4-HDHA, which mediates the anti-angiogenic effects of DHA. Strong biochemical data do indeed link low DHA retinal concentrations with degeneration and onset of vision disorders. This is especially important for the elderly and preventive strategies now rely on solid evidence. This notion was reinforced by one of the subsequent concurrent symposia, in which Drs. Yves Sauve´ and Martin-Paul Agbaga further reviewed our current knowledge on the roles of long chain omega 3 fatty acids and PUFAs in retinal function and degeneration. The overall conclusion (which echoes what was said by Dr. Gene Anderson at the Brighton ISSFAL meeting) is that we still have much to investigate to obtain a clear view of the precise roles of PUFAs in the retina. In particular, while there is extensive evidence that insufficient DHA intakes and/or altered retinal metabolism are strongly associated with
E-mail address: [email protected] 0952-3278/$ - see front matter http://dx.doi.org/10.1016/j.plefa.2012.07.001
macular degeneration, provision of omega 3 fatty acids did not prove to be a viable therapeutic option. Therefore, we need better understanding of transport systems and of the potential use of supplements to slow down or even revert retinal degeneration. The evergreen theme of saturated fats and cardiovascular health was discussed in one of the four parallel symposia that followed the first coffee break. Dr. Bob Gibson gave an interesting initial overview, using a fresh approach to the issue and trying to underscore the various confounders that undermine all epidemiological studies of saturated fats and health. The topic was subsequently expanded by Dr. Kim Jackson, who pointed to the fact that genetics plays a major role in individual response to dietary manipulation (in this case, with saturates). As an example, E4 are particularly sensitive to interventions with different fatty acids: the SatGene study is, in fact, designed to assess the impact of altered fat content and composition on the blood lipid profile according to the APOE genotype. Therefore, without knowing the individual genetic background, it appears difficult to propose general rules on the exact proportion of saturates that should make part of an optimal diet. Dr. Brian Rodrigues presented a series of very interesting studies on lipoprotein lipase(s), which are paramount in providing essential fuel to the heart. These enzymes are often being attributed with noxious properties and our knowledge of them appears to be rather limited. In diabetes, absolute or relative lack of insulin impairs cardiac glucose transport and oxidation, resulting in fatty acids becoming the preferred means of energy supply. This, in turn, starts a vicious cycle in which lipoprotein lipases become upregulated resulting in abnormal fatty acid supply and utilization by the heart tissue that could potentially initiate and sustain cardiac dysfunction. Therapeutic options are under scrutiny and might provide viable tools in the near future. Dr. Charles Serhan gave one of the two concurrent Plenary Lectures of Sunday afternoon. He extensively reviewed the multiple biological actions of resolvins, maresins, and protectins and presented new exciting data on their anti-microbial activities. Indeed, while the mechanisms of action are still to be elucidated and currently do not rest on biochemical hypotheses, the use of these fatty acid mediators allows decreasing the dose of antibiotics necessary to heal infected animals. Of course, these exciting data add to the plethora of interesting activities attributed to such lipid mediators. The conclusion that can be drawn is that resolution of acute inflammation is an active programmed process that also stimulates tissue regeneration. Provision of resolvins etc. basically speeds up the body’s natural reaction to inflammatory stimuli. Whether these compounds will ever enter into the pharmaceutical
54
ISSFAL Society News / Prostaglandins, Leukotrienes and Essential Fatty Acids 87 (2012) 53–56
realm is as yet to be proven, but – based on the available data – we can certainly envision the future use of EPA- and DHA-derived resolvins, maresins, and protectins as medicine. The controversy of whether omega 3 fatty acids exert antiarrhythmic activities has been addressed by Dr. Rozenn Lemaitre, who opened a parallel symposium on ‘‘Fatty Acids and Preventive Medicine’’. As a matter of fact, after the first positive reports, subsequent studies did not confirm the anti-arrhythmic activities of omega 3. Differences among methods, patient selection, individual needs and genetics might account for these discrepancies. As of today, we cannot really conclude that omega 3 fatty acids are anti-arrhythmic and further studies are necessary. In the same symposium, Dr. Kevin Maki reviewed the evidence linking hypertriglyceridemia to cardiovascular disease. As of today, no large-scale, prospective outcomes trial has been completed to evaluate the efficacy of lipid-altering drug therapy in patients specifically selected for the presence of hypertriglyceridemia. The best we can do is to extrapolate results from trials with statins, fibrates, and omega 3 fatty acids aimed at other patients. Interestingly, non-HDL cholesterol appears to be a better predictor of CV disease than LDL-cholesterol (see SM Boekholdt JAMA 2012). Therefore, ad-hoc trials are warranted and, in this respect, specific fatty acids might play interesting therapeutic roles. Interested readers might want to check a recent Mozaffarian review (J Nutr 2012) on the different effects of DHA and EPA (if there are any, as he concludes). Monday morning started with another Breakfast Workshop, which was sold out and I didn’t attend. This, however, tells us about the urgent need to ameliorate and standardize fatty acid analyses (see later under ISSFAL Membership Meeting). The second day of the meeting started with two concurrent plenary lectures. I attended the one given by Dr. James Ntambi, who reviewed the effects of fatty acids on gene expression and its regulation. In particular, his group is using the stearoyl-CoA desaturase (SCD) mouse model to investigate the role of de novo synthesized fatty acids in the regulation of lipogenic gene expression. In his lecture, Dr. Ntambi proposed hepatic MUFA as regulators of lipogenesis and gluconeogenesis, with oleate being more potent than palmitoleate. In a way this might in part explain the high incidence of obesity in high-MUFA consumers. Four parallel symposia followed. The one on Fatty Acids and Metabolic Regulation was chaired and opened by Dr. Jan Kopecky, who presented an overview of the role of omega 3 fatty acids in the treatment of the metabolic syndrome. His conclusions were that we still don’t know much about the exact role that omega 3 fatty acids might play in the development and/or the treatment of the metabolic syndrome. As an example, the relation of omega 3 with obesity is still not clear, even though these fatty acids decrease cell proliferation. In addition, omega 3 fail to improve glycaemic control in diabetic patients. In brief, omega 3 per se appear to be ineffective in the treatment of the metabolic syndrome. However, they might prove useful as adjunct treatment, for example by adding omega 3 to mild calorie restriction, which efficiently reduces body fat accumulation, while inducing a metabolic switch toward lipid catabolism in adipose tissue. Other mixed data were shown by the subsequent speakers. In particular, Dr. Anna de Boer showed how omega 3 decrease proinflammatory adipokine secretion in an interesting co-culture model of adipocytes and macrophages, hinting at anti-inflammatory effects. Dr. Michel Narce compared the effects of omega 3 (from linseed oil) and omega 6 (from sunflower oil) in livers of Zucker rats (a model of metabolic syndrome). While steatosis was decreased by the former, it was conversely increased by the latter, suggesting differential modulation of lipid liver biosynthesis and insulin sensitivity in the early state of metabolic syndrome. This presentation followed that of Dr. Darshan Kelley, who tested the effects of DHA supplementation
(3 g/d, 90 d) in the absence of EPA on glucocentric and lipocentric markers of insulin resistance in hypertriglyceridemic men. No dramatic functional effect was noted and the conclusion was that further studies are required to elucidate (or rule out) the role of DHA and omega 3 in this kind of patients. [contributed by Dr. Nathalie Nicod] The session on ‘‘Interesterified and novel fatty acid sources’’ was opened by Dr. Kalyana Sundram who gave a valuable overview on the nutritional outcomes of the interesterification of fats. Dr. Thomas Sanders followed by showing a study in which interesterifaction of palm oil had no adverse effects on cardiovascular risk factors. Fatty acid ethanolamides were introduced by Dr. Lin Lin, who showed that they associate with energy metabolism in humans. Dr. Sebastiano Banni followed by showing that a endocannabinoid balance between visceral and subcutaneous adipose tissues is crucial for body fat homeostasis and low doses of dietary n-3PC are able to significantly improve metabolic syndrome in obese Zucker rats. Aside from plenary lectures, one of the most attended sessions was the one on linoleic acid, which underscores the interest of the scientific community (namely, lipidologists) for this issue. Over the past few years, a heated though professional debate is developing over the health effects of omega 6 vs. omega 3 fatty acids. While some researchers claim that omega 6 fatty acids actually increase cardiovascular risk (notably via inflammatory actions), others argue the exact opposite, i.e. that omega 6 fatty acids decrease blood cholesterol and, hence, cardiovascular risk and mortality. The truth is that there are very few well-conducted randomized trials and that we often base our discussion on surrogate markers. This symposium – aptly named Linoleic Acid: Roles in Human Health and Requirements – addressed this hot topic with three highly-qualified scientists. The first one, Dr. Joe Hibbeln, formulated the hypothesis that endocannabinoids and their receptors can be modulated by linoleic acid and, therefore, lead to dissatisfaction, hunger, increased needs to be satisfied, and, in turn, increased obesity. Indeed, soybean oil (one of the two most popular oils worldwide) is the only food item associated with increased obesity. This challenging view pairs with the increased levels of consumption of linoleic acid witnessed in the Western world over the past decades. Moreover, alpha-linolenic acid consumption in the East is associated with decreased cardiovascular mortality, whereas linoleic acid consumption is not. According to Dr. Hibbeln, linoleic acid increases cardiovascular risk, as indicated by several striking correlation between intakes and epidemiology. To gain mechanistic insights over the potentially noxious effects of linoleic acids and omega 6, Dr. Kevin Fritsche reviewed randomized controlled trials that permitted the assessment of dietary linoleic acid on biological markers of chronic inflammation. Fifteen studies (eight parallel and seven cross-over) met inclusion criteria. None of the studies reported significant findings for a wide variety of inflammatory markers including C-reactive protein, fibrinogen, plasminogen activator inhibitor type 1, cytokines, soluble vascular adhesion molecules or tissue necrosis factor-alpha. Therefore, as of 2012, there is no evidence from randomized, controlled intervention studies among healthy, noninfant humans to show that variations in the level of linoleic acid in the diet affect in vivo inflammation in healthy humans. It is noteworthy that most trials include small numbers of participants, are of short duration, and usually do not report on alpha-linolenic acid intakes. Given that linoleic acid intake lowers plasma cholesterol, its putative negative effects on cardiovascular mortality are puzzling. To further fuel the debate, Dr. Christopher Ramsden re-analyzed data from the Sydney Heart Trial, a secondary prevention trial that selectively tested safflower oil without confounders such as short chain omega 3 fatty acids. The results show that this treatment increased all-cause and cardiovascular mortality. Inclusion of these data to a meta-analysis of the effects of fatty acids on mortality leads to the conclusion that provision of linoleic acid
ISSFAL Society News / Prostaglandins, Leukotrienes and Essential Fatty Acids 87 (2012) 53–56
non-significantly increases overall mortality in all trials and significantly increases mortality in secondary prevention trials. There are numerous caveats to be taken into account: these trials adopted high doses of PUFAs, often included few subjects, do not account for unknown confounders, and might not apply to the general population. The overall conclusions of Dr. Ramsden were that the term ‘‘PUFA’’ means very little in terms of human health, that we should stress that health benefits are conveyed by EPA and DHA, that – in vivo – it is difficult to disentangle the individual effects of linoleic and alpha-linolenic acid (normally both present in vegetable oils), and that there are no proven benefits of the former, which might actually increase mortality rate. Of course, as I mentioned earlier, this is a highly-debated topic that does indeed require more investigation (however costly and difficult to perform). Biochemical bases are also strong in theory, but weak in practice, confounders are difficult to eliminate, and sometimes individual bias and ideas lead to misinterpretation. In short, do make an effort to attend future ISSFAL meetings to keep up with the latest news. During lunch break/poster session, Dr. Bob Gibson chaired a very interesting session devoted to a ‘‘three minute thesis competition’’. As the title suggests, selected students had a chance to present their work in a condensed way. This session was very well received, lively, and educational at the same time. The meeting resumed with the Alexander Leaf Award Lecture, given by the recipient Dr. Bob Gibson, who gave an historical overview of his studies on maternal nutrition, with particular focus – of course – on fatty acids. Mixing history, old photographs of him and his mentors and colleagues, biochemistry, clinical trials, failure and success, Dr. Gibson’s entertaining lecture was a clear example of how science and biomedical research progress. Younger attendees did certainly learn important lessons from this lecture. Of the two concurrent Plenary Sessions that followed, I chose that of Dr. Klaus Gawrisch, on membrane lipid–protein function. One of the things I learned is that membranes are so fluid they constantly move and fluctuate. Their packing into the classical bilayer puts them under tensile stress. Modulation of membrane fluidity by fatty acids heavily influences G protein-coupled membrane receptors (GPCR), which comprises receptors for dopamine, serotonin, epinephrine, opioids, cannabinoids, etc. These receptors can be reconstituted to study their modifications by individual fatty acids and predict – to a certain extent – how the cell would react to stimuli once we modify its lipid composition. Four parallel symposia followed. I managed to attend two of them (though not at the same time y). In the first one, Dr. Grant Pierce illustrated the Flax-PAD study, a large (though he calls it small) clinical study on the effects of flaxseed (rich in alphalinolenic acid) in patients with peripheral arterial disease. In this trial, bread and muffins added with linseed were provided to patients, who witnessed a decrease in blood cholesterol and a remarkable decrease in systolic and – to a slightly lower extent – diastolic blood pressure. The magnitude of this effect is stronger than that of other dietary interventions and is comparable with some anti-hypertension drugs. The effects of alpha-linolenic acid were also studied by the group of Dr. Lindsay Brown. In particular, they studied chia oil, of which Australia is the principal producer. Their results show that, in rats, chia oil improves cardiac and hepatic functions when animals are fed a high-fat, high-sugar diet to induce approximation of metabolic syndrome. In the adjacent room, our Editor in Chief Dr. Richard Bazinet outlined his studies on cerebral uptake of fatty acids. The most interesting findings are that the brain vary rapidly beta-oxidizes EPA (which might explain why its levels are so low) while maintaining a tight homeostasis of DHA. Indeed, it takes months
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to replace cerebral DHA (which also shows selected incorporation into areas and phospholipids, as recently published by yours truly). These studies will help proper targeting of adjunct therapy with omega 3 fatty acids in neurological disorders. The final talk was given by Dr. Gunter Eckert, who treated aged mice (who have lower brain DHA levels) with long-chain omega 3 fatty acids and showed improved mitochondrial respiratory chain (especially complex IþII and IV activities) and ATP production. After the now traditional ‘‘Meet the Professors’’ breakfast, organized by Dr. Richard Bazinet, two plenary sessions opened the Tuesday section of the meeting. In one of them, Dr. Patrick Tso gave a very interesting, didactic, and entertaining lecture on how we digest and transport triacylglycerols. His lecture spanned from the roles of gastric lipase and pancreatic lipase to the mechanism of chylomicron formation in the enterocytes and the role of various apolipoproteins in intestinal lipid transport by the enterocytes. Answering several questions, Dr. Tso further illustrated the biochemical pathways involved in fat absorption (which is way more complex than I thought). [Contributed by Dr. Nathalie Nicod] A very interesting and diverse symposium was the ‘‘President’s hot topics session’’, in that it brought up-to-date insights to fatty acids and nutrition. Dr. Rinat Ran-Ressler started the session with a very interesting talk on the effect of branched chain fatty acids (BCFA) on necrotizing enterocolitis (NEC). BCFA are found in the normal term human newborn gut, deposited as major components of vernix caseosa and ingested during late fetal life. The researchers fed pups with 20% BCFA and found that NEC incidence was reduced by 56% and the composition of the microbiota was altered in the BCFA group compared to the control group. Dr. Adina Michael-Titus demonstrated that after thoracic compression, FAT-1 mice, which can synthesize DHA, display better functional locomotor recovery compared with the wildtype mice on a high omega-6 diet and WT mice on a normal diet. This improved neurological outcome was associated with a significant increase in neuronal and oligodendrocyte survival. Dr. Anne Marie Minihane showed an interesting association between genotype and diet. Her group found a greater sensitivity of plasma lipids and CRP to dietary fat quantity and composition, in APOE4 carriers (E3/E4), relative to E3/E3 genotype. Although both genotypes benefited from the TG lowering effects of DHA, E3/E4 individuals showed a more marked response, indicating additional hypotriglyceridaemic benefit in this large population subgroup. Thus, they suggest that the E4/E4 population might be even more responsive to diet. N-acyl-phosphatidylethanolamines (NAPEs) are normally synthesized in the small intestine and their metabolites increase satiety and decrease food intake. Dr. Sean Davies showed that mice fed a transformed Escherichia coli that catalyzes NAPE formation gained 29% less weight then controls with a decrease in body fat and not lean mass, due to a lower intake. These remarkable results suggest that manipulation of the microbiota may help treat obesity. Dr. Gregory Shearer ended the session by presenting the changes in specific lipoprotein oxylipins in Metabolic Syndrome, and concluded that omega-3 ethyl ester treatment corrects or hypercorrects these changes and thus oxylipins are likely to improve lipoprotein signaling. The ISSFAL Early Career Award was given to our Associate Editor Dr. S. Raza Shaikh, who is studying lipid rafts and the role of fatty acids in membrane physiology. One of his most interesting observations is that DHA, which greatly changes membrane’s properties, does incorporate into lipid rafts, although it does not do so easily because it does not bind cholesterol and because of steric incompatibility. However, once DHA is made part of the raft, it stabilizes it and creates more ordered structures.
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ISSFAL Society News / Prostaglandins, Leukotrienes and Essential Fatty Acids 87 (2012) 53–56
Following the Early Career Award, another important ceremony took place, i.e. the New Investigator Award. Drs. Melissa Gregory, Zacharoula Nikolakopoulou, and Sarah Orr were given this important ISSFAL awards and were chosen among several outstanding young investigators who are developing their independent career. This award confirms ISSFAL’s mission to support investigators in the area of fatty acids and lipids and to create opportunities for young scientists to carry out high-quality research. One of the milestones of every ISSFAL conference is the Membership Meeting. This is a unique opportunity for ISSFAL members to meet with the Executives and propose ideas to further develop our society. In this occasion, some suggestions have been made to have a successful ISSFAL 2014 (in Stockholm). Examples included topics, organization of symposia, etc. One general question was asked about the use of PLEFA as our official journal. It needs to be remembered that PLEFA and ISSFAL interact in that building a strong journal largely depends on ISSFAL members. With a strong and widely-read official journal, ISSFAL will also grow further in status and membership. Therefore, members are encouraged to submit high-quality manuscripts to PLEFA and to cite PLEFA papers whenever possible. As a matter of fact, the 2011 Impact Factor is 3.4, i.e. it doubled as compared to the 2010 one, which is exactly the result of high-quality submissions and ever-increasing citations. Other issues concerned membership (on the rise) and financial status (solid). Finally, it was proposed to create a consensus over fatty acid analysis and come up with an ‘‘ISSFAL-endorsed’’ methodology that should be followed worldwide. We tried to do this before via the newsletter and the response was [euphemistically] less than enthusiastic. The idea, however, is worth pursuing so stay tuned for future developments. One innovative feature of ISSFAL 2012 was the participation of scientists/opinion leaders who work in areas collateral to our own
biomedical research. One notable example was that of Dr. Villy Christensen, who gave a rather worrisome overview of the fishing industry and the challenges we are facing to maintain our oceans healthy and full of fish. Apparently, quite the converse is happening: overfishing is stressing the aquatic environment and the future is not bright. Several initiatives are being taken: one of them is the Nereus Program (http://www.nereusprogram.org/ content/nereus-ocean-visualization), a think-tank which brings together several stakeholders to address the issue of over-exploitation of the world’s fish resources. Although immediate, clear actions are not being proposed, this international research and outreach network is focused on understanding the status of the global ocean and how we can ensure that there will continue to be seafood and a healthy ocean. We will certainly follow its future developments. One of the final two concurrent plenary sessions featured Dr. Parveen Yaqoob, who talked about fatty acids and immune function. Her conclusion was that fatty acids do influence immunity in different ways. The extent and precise nature of such influence is still unclear, especially in vivo. One example she illustrated is that of the FAT-1 mouse, which is protected from colitis, but experiences higher incidence of pulmonary tuberculosis. In humans, the picture is even more unclear and we need further investigation, especially in the elderly where the immune function is often compromised. In conclusion, ‘‘Well done!’’ to the organizers and the sponsors (which can be found in the ISSFAL 2012 website) for this flawless meeting which, as always, brought together the very best of lipid science, once again intermingling solid science with friendly exchange of projects and friendship. We will all see each other again in 2014 in Stockholm, where preparations by Dr. Brigitte Strandvick and her collaborators are already at an advanced stage.