what process is used to change an unsaturated fat to a saturated fat?
Adv Nutr. 2015 May; vi(three): 293S–301S.
The Science of Fatty Acids and Inflammation1, 2, 3
Abstract
Inflammation is believed to play a fundamental role in many of the chronic diseases that characterize modern lodge. In the past decade, our agreement of how dietary fats affect our immune arrangement and after our inflammatory status has grown considerably. There are compelling information showing that high-fatty meals promote endotoxin [e.g., lipopolysaccharide (LPS)] translocation into the bloodstream, stimulating innate allowed cells and leading to a transient postprandial inflammatory response. The nature of this effect is influenced past the amount and type of fat consumed. The role of various dietary constituents, including fats, on gut microflora and subsequent health outcomes in the host is another heady and novel area of research. The impact of specific fatty acids on inflammation may be key to how dietary fats touch health. Iii key fatty acrid–inflammation interactions are briefly described. First, the evidence suggests that saturated fatty acids induce inflammation in part by mimicking the actions of LPS. Second, the frequently-repeated claim that dietary linoleic acid promotes inflammation was not supported in a recent systematic review of the evidence. Tertiary, an explanation is offered for why omega-3 (n–3) polyunsaturated fat acids are so much less anti-inflammatory in humans than in mice. The article closes with a cautionary tale from the genomic literature that illustrates why extrapolating the results from inflammation studies in mice to humans is problematic.
Keywords: fatty acids, inflammation, endotoxin, linoleic acid, omega-3, microflora, lipopolysaccharide
Introduction
Inflammation is an essential component of the host response to infection or injury (i, 2). The inflammatory response involves the interactions among and betwixt many dissimilar jail cell types. The archetype symptoms associated with inflammatory responses include oestrus, redness, swelling, pain, and loss of office. Typically, inflammation is meant to be transient, merely nether some circumstances the astute response can become chronic (3). Excess chronic inflammation is an of import etiologic factor in a wide range of common chronic diseases, including cardiovascular illness (four), diabetes (iv), Alzheimer and other neurologic diseases (5), and cancer (6). Inflammatory responses result in local and systemic product of numerous soluble products, including C-reactive poly peptide (CRP)four, TNF-α, IL-vi, serum amyloid A, and plasminogen activator inhibitor i, among others (7). Numerous epidemiologic studies take reported associations between one or more of these biomarkers and the risk of various chronic diseases. All the same, there is no consensus regarding which inflammatory biomarker is best. Instead, it appears that many researchers mensurate multiple biomarkers in any given study to increase the odds that associations with clinical outcomes will emerge. Chiefly, recent reports provide support for the thought that different diseases are associated with specific inflammatory biomarker profiles, which relates to dysregulation of specific immune cell populations (8, 9). In the hereafter one hopes that disease-specific inflammation biomarkers volition be conspicuously divers. In the concurrently, readers interested in gaining a better understanding of the many issues surrounding biomarker pick are encouraged to read the written report of the European branch of the International Life Sciences Institute, which commissioned a review of the biomarkers for monitoring inflammation in human nutritional studies (10).
There exists a big trunk of bear witness suggesting that a diversity of dietary factors tin raise or diminish inflammation (11). The focus of this article is to depict how dietary fats bear upon inflammation and why information technology is an of import human wellness consideration. Current dietary guidelines for fats provide information almost both the amount as well equally the types of fats that should exist consumed (12). Because fats are energy dense, the guidelines set an upper limit of 35% of total calories from fats. The primary goal of setting this upper limit is to reduce the gamble of developing obesity, a condition associated with elevated concentrations of several inflammatory biomarkers, including CRP and TNF-α (13).
Evidence suggests that, in addition to the amount of fat, the types of fats consumed can have a major affect on man health. Their impact on the risk of cardiovascular affliction has dominated the rationale for these recommendations for the past fifty y (14–xvi). There is a growing recognition past leaders in the nutrition and wellness field that dietary fats can impact host inflammatory responses (17). After reviewing the evidence, information technology seems reasonable that the bear upon of dietary fats on inflammatory status be factored into hereafter dietary guidelines for these nutrients.
Current Status of Noesis
It appears that 1 mode in which dietary fat is linked to inflammation is by promoting the translocation of microbial products from the gut into the bloodstream. Bourgeois estimates advise that in that location are >100 trillion commensal (i.east., normal) organisms in the gut (18). These microorganisms, collectively referred to as the "gut microbiome," contain >1 g of LPS. LPS is also referred to as endotoxin, because it is an endogenous component of the prison cell wall of all gram-negative leaner and it tin can have "toxic" effects in nigh mammals (19). LPS is a very stiff stimulus of inflammatory responses, with bioactivity in the microgram per liter concentration range. Chiefly, there exists considerable diversity in the structure and bioactivity of LPS from microbial species (20). This diversity suggests that private gut microbiomes may exist more or less proinflammatory on the basis of how effectively innate immune receptors recognize these microbially derived agonists.
Researchers accept known for decades that gut microbes could exist a source of systemic bacterial infection leading to sepsis and organ failure nether a diverseness of medical circumstances (21). Notwithstanding, it was only recently that researchers reported that dietary fat could promote endotoxin absorption. Cani et al. (22) reported that feeding mice a diet very high in fat (i.due east., 72% of total free energy) over 4 wk significantly elevated circulating endotoxin concentrations compared with mice fed a depression-fat control nutrition. The data advise that high-fatty feeding results in a chronic tiptop in circulating endotoxin throughout the twenty-four hour period and night. The authors reported that the loftier-fat diet altered the distribution and numbers of some of the microbial populations institute in the gut. Interestingly, the authors went on to demonstrate that high-fat feeding afflicted a number of metabolic processes associated with metabolic syndrome (e.1000., hepatic TG accumulation, elevated fasting insulin, visceral adipose tissue accumulation) in a style like to infusion of LPS. Elevated expression of a number of inflammation biomarkers, such every bit TNF-α, IL-1, and IL-vi, was observed in the liver, adipose, and muscle. These responses were surprisingly similar in mice infused with LPS compared with those fed the high-fat nutrition. However, it was the authors' apply of mice carrying a deletion of CD14, a critical component of the LPS receptor, which provided the about compelling show that many of the adverse effects of loftier-fat feeding may exist a consequence of activation of inflammatory signaling pathways.
Current thinking is that the acute postprandial inflammatory response associated with fat consumption is mediated past endotoxin, primarily derived from gut microflora (23). Others suggested, however, that many foods contain endotoxin or related proinflammatory compounds that, upon assimilation, direct stimulate inflammatory responses (24). Those foods with the most in vitro inflammatory action included meats, cheeses, and dairy products. Regardless of source, once absorbed, endotoxin is shuttled between chylomicrons and HDL particles via a specific binding proteins and soluble receptors present in the circulation (25).
Rodent studies bespeak that the structure/form of the dietary fatty affects how much endotoxin is absorbed (26). There is a strong correlation between postprandial lipemia and internet endotoxin absorption. Evidence suggests that chylomicrons play a disquisitional function in the absorption and transport of endotoxin. Factors that promoted fat absorption, such as emulsification, too enhanced endotoxin absorption. Recently, Mani et al. (27) demonstrated that fatty source afflicted postprandial endotoxin absorption and send in the sera of domestic pigs. After overnight feed deprivation, pigs were fed a meal containing 12.five% by weight (∼25% of total energy) added fat or saline (control). The meal was consumed inside x min, so blood samples were taken hourly for 5 h. Pigs fed coconut oil, rich in SFAs, had the highest circulating concentrations of endotoxin followed by those that were fed vegetable oil and then those fed fish oil. Additional testing on freshly isolated samples of ileum showed that the fats had non affected overall intestinal integrity or permeability. The authors suggested that the endotoxin absorbed was nearly likely transported past style of lipid raft–mediated endocytosis.
However, not all fat claiming studies reported significant findings. Tousoulis et al. (28) examined the affect of a unmarried tour of fat/oil consumption on inflammation using soluble vascular jail cell adhesion molecule one assessment. Good for you subjects (n = 37) were randomly assigned to receive 50 mL of water or oil (e.g., corn oil, extra-virgin olive oil, soy oil, or cod liver oil). The authors constitute no statistical differences between treatment groups for circulating soluble vascular prison cell adhesion molecule 1 either pre- or post-treatment. The authors' reliance on a single inflammatory biomarker is an important limitation of this study.
The selection of multiple inflammatory biomarkers, however, is still no guarantee that handling furnishings will be observed. For example, Voon et al. (29) monitored circulating TNF-α, IL-1, IL-6, IL-8, and CRP in 45 healthy human subjects who participated in a randomized crossover intervention study. Iii different examination fats were examined for their impact on circulating cholesterol and inflammatory status. The test fats included a palmitic acid (16:0, hexadecanoic acid)–rich palm oil, coconut oil (rich in 12:0 + 14:0, dodecanoic + tetradecanoic acids), and virgin olive oil [rich in oleic acid (eighteen:1, octadecenoic acid)]. The hypothesis was that fats rich in SFA, such every bit coconut and palm oils, would enhance circulating biomarkers of inflammation, and thus the inflammatory status of these healthy subjects. Fasting and nonfasting (2 h postprandial) blood samples were nerveless v wk after the start of the dietary interventions. The macronutrient content of the examination diets were maintained at 20% of energy from poly peptide, 30% from fat, and 50% from carbohydrates. The results failed to demonstrate whatsoever significant impact of fat source on any of these circulating biomarkers of inflammation. The well-nigh instructive aspect of these data was the significant inter- and intraindividual variation that was noted for these inflammation biomarkers. Every bit a consequence of this variation, many such studies suffer from being underpowered.
Conspicuously, not all fats under all circumstances promote postprandial inflammation. There are insufficient information to predict when and how specific fatty sources will affect inflammatory status in people. One possible explanation for the discrepancies in the literature is the variability in the types of microbes in the gastrointestinal tract of individuals being studied in these postprandial fat challenge studies. Recent advances in our understanding of how the gut microbiome adapts to changes in human being ecology over time are particularly relevant in this context (thirty). It was suggested that the increasing incidence of allergic and metabolic disorders (e.thou., obesity, blazon 2 diabetes) in immigrant populations every bit they adopt Western dietary patterns is linked to shifts in gut microbial populations. Whether this tin can explain why some individuals are more than sensitive to systemic inflammation upon a fat challenge is unknown.
Recent findings suggest that dietary fats can influence gut microflora limerick and that this can affect inflammatory status in vivo (31). In a contempo study the effects of 3 different dietary fat sources on the normal microflora of C57BL/6 mice were examined (32). When compared with lard, milk fat (MF) and a PUFA-rich fat had like effects on Bacteroidetes and Firmicutes; nevertheless, a big increase in a fellow member of the Deltaproteobacteria, Bilophila wadsworthia, was consistently observed only with MF. Interestingly, these microbiota changes differed from those induced past lard-based SFAs.
To demonstrate the clinical relevance of such a shift in gut microflora, the researchers conducted a follow-upwards study with a strain of mice that are susceptible to developing inflammatory bowel disease (i.e., Il10–cipher mice). Only MF consumption promoted colitis and inflammatory cytokine expression in the distal colonic mucosa of these Il10–nothing mice. These researchers went on to show that the mechanism by which MF afflicted gut microflora was related to changes in hepatic bile acrid production (see Figure 1 ) (33). Whether dietary fats substantially affect inflammatory status of people past altering their gut microflora remains untested, but with the rapid advances in the field, answers should exist forthcoming.
Pathway from consuming milk fat to colitis by way of altered bile acid product and subsequent shifts in gut microbial populations. Reproduced from reference 33 with permission.
Apart from their role in promoting the uptake of endotoxin in the gut, many researchers believe that dietary fats are able to affect inflammation by more direct ways. For case, information technology has long been known that SFAs are an essential structural component of bacterial endotoxins (19). The lipid A portion of all pathogenic LPS contain 6 ester- and/or amide-linked saturated fat acyl groups. The length of the acyl chains in lipid A ranges from 12 to 16 carbons. The commutation of SFA with MUFA or PUFA eliminates the proinflammatory activeness of LPS. Macrophages, and other cells of the innate immune organization, possess receptors [i.due east., toll-similar receptor (TLR) iv] that recognize LPS (34). LPS-mediated signaling through TLR4 leads to the activation of NF-κB, a transcription factor, that subsequently turns on the expression of numerous proinflammatory cytokines, such equally TNF-α, IL-1, IL-6, and IL-8. TLR4 is part of a larger family of receptors responsible for recognizing pathogen-associated molecular patterns (35). More than than a dozen TLRs have been identified in humans and mice. These receptors are expressed throughout the body and are critical for host defense against invading pathogens.
In 2001, Lee et al. (36) were the first to demonstrate that SFAs were able to direct stimulate inflammatory gene expression by style of TLR4 signaling in vitro. The relative authorisation of various SFAs varied with chain length, with lauric acid (12:0) showing the greatest activity, whereas myristic acrid (14:0) and stearic acid (eighteen:0, octadecanoic acid) appeared to have surprisingly fiddling proinflammatory activity. In dissimilarity to SFAs, MUFAs and PUFAs failed to actuate TLR4 signaling. Interestingly, these researchers were able to bear witness that pretreatment of cells for 3 h with a variety of PUFAs or oleic acid (octadecaenoic acid; 18:1n–ix) significantly reduced the subsequent proinflammatory outcome of lauric acid treatment. They went on to prove that the power of PUFAs to block inflammatory responses induced past LPS or lauric acid was dependent on TLR4.
A few years later on, this aforementioned group examined the bear on of FAs on TLR2 signaling (37). TLR2, like TLR4, is a strong stimulator of inflammatory responses. Microbial components that are stiff agonists for TLR2 include di- and triacylated lipoproteins, peptidoglycans, and lipoteichoic acrid. It turns out that TLR2 but functions as part of a heterodimer with either TLR1 or TLR6. The rationale for exploring the potential of FAs to affect TLR2 signaling arose from the results of a written report these researchers conducted with innate immune cells from TLR4-mutant mice. When bone marrow cells from TLR4-null mice were differentiated into macrophages and so treated with lauric acid the authors observed upregulation of cyclooxygenase ii Ptgs2 expression, an inflammatory gene. Considering these cells did non express TLR4, LPS treatment was without upshot on cyclooxygenase 2 expression. These authors found that lauric acid stimulated TLR2-mediated signaling only when TLR2 was coexpressed with TLR1 or TLR6. In contrast to lauric acid, DHA (22:6n–iii, an north–3 PUFA) treatment tended to diminish microbial agonist-mediated signaling of a wide variety of TLRs. More will be said about the anti-inflammatory activeness of DHA in the section on northward–iii FAs.
Linoleic acid (LA; eighteen:2n−half-dozen, octadecadienoic acrid) is an north–half-dozen PUFA and an essential food (38). LA comprises ≥50% of the nigh widely consumed vegetable oils in Western societies. For many decades it has been known that LA helps reduce blood cholesterol concentrations and that substituting LA for SFAs lowers the gamble of center illness (39). Therefore, current recommendations from numerous expert bodies, including the Institute of Medicine and the American Middle Clan, are that people should eat betwixt 5% and 10% of full energy equally LA for a eye-healthy nutrition (40).
Withal, a few members of the lipid research community have expressed concerned that LA-rich diets are unhealthy and promote inflammation (41, 42). The theoretical ground for this concern over LA's proinflammatory deportment involve a number of putative interrelated metabolic processes, including the following: 1) dietary LA promoting tissue arachidonic acid (AA; twenty:4n−6, eicosatetraenoic acid) aggregating, 2) enhanced synthesis of proinflammatory eicosanoids derived from AA, three) reduced conversion of α-linolenic acid (ALA; 18:3n−3, octadecatrienoic acrid) into EPA (eicosapentaenoic acid; 20:5n–3) and/or DHA, and 4) macerated synthesis of anti-inflammatory eicosanoids from EPA and DHA. The experimental testify supporting each stride of this prototype originated primarily from rodent and cell culture studies. More recently, and in contrast with the multistep procedure described above, it was suggested that various oxidized forms of LA are straight responsible for stimulating inflammation (43).
Fortunately, the beginning testify-based review of all the man clinical data bachelor that addressed the touch of dietary LA on inflammation in good for you adults was recently published (44). Fifteen studies (8 parallel and vii crossover) met the inclusion criteria. The about important inclusion criterion was that the only FA other than LA that was allowed to differ essentially between the experimental and control dietary interventions was oleic acid. The reason for this was the existing evidence that suggested that oleic acrid had no impact on inflammation (45). In contrast, information technology is believed that SFAs promote and north–3 PUFAs reduce inflammation; thus, simultaneous changes in the intake of those FAs forth with LA could confound interpretation of the results. Heterogeneity betwixt these studies prevented meta-analysis. Regardless of this limitation, not one of the studies reported a pregnant positive association betwixt LA intake and circulating concentrations for a wide variety of inflammatory markers. More than frequently than not, higher LA intake was associated with lower, not college, inflammatory status in healthy adults. In addition, the results from a randomized controlled trial, which was completed and published later on the systematic review, indicated that increasing LA intake from 4% to 13% of energy improved (i.e., diminished) biomarkers of inflammation in obese subjects (46). Not surprisingly, those subjects consuming extra SFAs from butter showed elevations in plasma markers of inflammation.
So an important question is why did the evidence from man clinical trials fail to back up the theory that dietary LA promotes inflammation? One reason might be that the "LA-proinflammatory paradigm" relies on an overly simplified model of LA metabolism. Originally, most of the proinflammatory action of dietary LA was idea to be a outcome of an accumulation of AA, which leads to greater production and release of proinflammatory eicosanoids, such every bit PGEtwo and leukotriene B4 (LTBfour). A review of the clinical literature by Rett and Whelan (47) indicated that increasing LA up to vi-fold within the context of a typical Western nutrition failed to increase tissue AA. Surprisingly, reducing dietary LA down to 10% of command was without effect on circulating AA. Therefore, for those who currently advocate for large reductions in dietary LA, their accent has shifted to the potential agin effects of oxidized forms of this PUFA. Recent advances in belittling capabilities (i.e., lipidomics) take greatly expanded our knowledge of LA-derived metabolites (48). All the same, our agreement of the bioactivity and physiologic function of each of these novel metabolites remains incomplete. Effigy 2 is meant to capture some of this complexity, at to the lowest degree as information technology relates to LA. Unfortunately, this author is unaware of a single publication that describes a research study in which all of the possible bioactive metabolites of LA and other important FAs have been measured and accounted for. Ii excellent reviews related to this topic were recently published (49, l).
LA and AA metabolites play roles in both inflammation and resolution. Solid lines betoken proinflammatory pathways, and dotted/dashed lines represent anti-inflammatory/proresolving pathways. AA, arachidonic acid; CYP450, cytochrome P450; EET, epoxyeicosatrienoic acids; HETE, hydroxyeicosatetraenoic acid; HODE, hydroxyoctadecadienoic acid; LA, linoleic acrid; LO, lipoxygenase; LTB4, leukotriene Biv; LTX, leukotoxin; NO, nitrosylated; PGE2, prostaglandin E2.
Much has been written about the potential health benefits associated with increasing our intake of n–iii PUFAs, including improved neurologic and cardiovascular health and diminished inflammation (51–53). n–iii PUFAs are a group of structurally related FAs. ALA is an eighteen-carbon n–3 PUFA from which all other due north–three PUFAs can be produced through a series of metabolic steps. Like LA, ALA is considered to be an essential nutrient for humans and nearly animals. DHA is the terminal terminate product of ALA elongation and desaturation (54). Although DHA is establish in the highest concentrations in the brain and retina, it can be plant in every cell membrane. Although consumption of ALA is an inefficient means for enriching cellular DHA content, consuming preformed DHA from various marine products (e.one thousand., fish oil) can issue in substantial increases in cellular DHA and EPA content (55).
Importantly, DHA modulation of immune prison cell function and subsequent inflammatory response are idea to exist a outcome of ane or more of these iii deportment. First, DHA (and EPA) are precursors for anti-inflammatory, proresolving lipid mediators known as resolvins, docosatrienes, and protectins (56). The anti-inflammatory action of these dual-acting lipid mediators is a event of their promotion of neutrophil apoptosis and monocyte recruitment. These monocytes differentiate into macrophages that efficiently engulf the apoptotic neutrophils and depart the inflammatory site by way of the lymphatic system. The novel concept that resolution is not but the absence of inflammation but a circuitous process that involves a programmed serial of steps has simply recently go widely accepted. Chiefly, in addition to DHA and EPA, AA-derived lipid mediators (i.e., lipoxins) also play an important function in programming resolution.
2d, DHA is believed to bear upon lipid microdomains within jail cell membranes (i.e., lipid rafts) that play a part in immune prison cell signaling pathways critical to inflammation (57). These researchers reported that, although lauric acid promoted, DHA diminished the recruitment of TLR4 into lipid raft fractions after LPS treatment. This DHA action reduced TLR4 homodimerization and subsequent signaling through this primal proinflammatory pathway. The power of DHA to affect the physical properties of cellular membrane microdomains has been shown for a variety of jail cell types (58). DHA-mediated alterations in membrane structure tin induce apoptosis in cancer cells, but its furnishings are highly dependent on the cell blazon and the molar concentration of DHA inside membrane phospholipids.
A third possible machinery of action for DHA (and EPA) relative to their anti-inflammatory activity recently emerged from the laboratory of Olefsky and coworkers (59). They reported that a novel G protein–coupled receptor 120 (GPR120) serves every bit a receptor/sensor for DHA (and to a bottom extent, EPA). Using a mouse macrophage cell line (i.e., RAW 264.7 cells) they demonstrated that stimulation of GPR120 with DHA or a chemical agonist resulted in a greatly diminished inflammatory response from these cells. By using small interfering RNA–mediated knockdown of GPR120, they were able to completely abrogate the anti-inflammatory activity of in vitro DHA treatment. The fact that nigh of the data generated in these studies used 100 μmol/L DHA, a concentration that profoundly exceeds physiologic norms, raises some concerns virtually the bodily role of GPR120 in vivo. The evidence that GPR120 is specific for DHA (and EPA) remains uncertain in light of the limited nature of the bodily dose-response curves presented and the fact that palmitoleic acid (16:1n–vii, hexadecenoic acid) was simply virtually as effective as DHA (59).
Regardless of which mechanism might explain the anti-inflammatory role of DHA, it would exist reasonable to presume that when exploring the touch on of dietary interventions on DHA-mediated allowed and inflammatory responses, the molar concentration and the magnitude of change in membrane DHA content would be disquisitional factors in determining to what extent cellular responses are altered. It is here where in that location is an important departure between mice and humans. Specifically, immune cells from mice start out with higher concentrations of DHA and, upon exposure to dietary DHA, the levels of enrichment in allowed cell membranes far exceed what is possible in homo immune cells (run across Figure 3 ) (lx). The dramatic accumulation of DHA in murine allowed cells probable affects lipid rafts and cell signaling in ways that are non reproduced in the more modestly enriched human being allowed cells. Turk and Chapkin (61) illustrated how DHA enrichment might bear upon membrane-based lipid rafts (see Figure 4 ). These and other experts in the field (62) have discussed the dose-dependent nature of n–3 FAs on a number of health conditions, including inflammation. In addition, the lower concentrations of cellular EPA and DHA in human immune cells would in all likelihood result in more than modest production of the anti-inflammatory lipid mediators than that produced by murine cells. Unfortunately, quantitative analyses of these lipid mediators accept not been reported to date. These cardinal species-dependent differences may assistance explain why dietary fish oil, a rich source of DHA, has such a powerful beneficial bear on on a variety of inflammatory atmospheric condition in mice, whereas human clinical trials have shown much more modest benefits, if any.
Quantitative comparison of dietary DHA with immune jail cell DHA from mice, rats, and humans. The data were from studies that met the following criteria: 1) dietary due north–3 PUFA (i.e., EPA and/or DHA) intake was a dependent variable in the study pattern, 2) the FA contour of an identifiable immune jail cell population was reported, and three) data were published and identified in PubMed (National Library of Medicine) through December 2005. n–3 PUFA intake is expressed as a percentage of total energy consumed (i.e., en%). In most studies, daily caloric intake was not reported. Thus, the following assumptions were fabricated: 1) human subjects consumed 2000 kcal/d and ii) rodents consumed the same calories across nutrition treatment groups. Best-fit lines/curves with 95% CI displayed by dotted lines were generated by using Prism software version 4.0b (GraphPad). Reproduced from reference 60 with permission.
Putative model for the effect of n–3 PUFAs on lipid rafts. Lipid rafts are nanoscale regions of the plasma membrane, enriched in cholesterol, sphingomyelin, and phospholipids containing saturated acyl chains. Both transmembrane and peripheral membrane proteins tin can be localized to lipid rafts. Upon treatment with a combination of north–3 PUFAs or DHA alone, these PUFAs are incorporated into phospholipids, which are inserted into both raft and nonraft regions of the plasma membrane. This results in enhanced clustering of lipid raft regions, which are depleted of cholesterol and sphingomyelin. In addition, many lipid raft–associated proteins "mislocalize" to the bulk membrane domain. This results in a suppression of lipid raft–mediated processes, including T cell activation and downstream signal transduction. Reproduced from reference 61 with permission.
Recently, a comprehensive analysis of the disparity between mouse and human responses relative to the potency of dietary n–iii PUFAs to affect inflammatory conditions was published (63). Consistent with the refractory nature of human immune cells to incorporate DHA into their membranes, one would predict that dietary intake of DHA would need to be much higher than what would be required to modulate allowed cell part in mice, whose allowed cells are more easily enriched with n–3 PUFAs. In fact, that is exactly what the author concluded: "In adult humans, an EPA plus DHA intake >ii g/d seems to be required to elicit anti-inflammatory actions." Because such intake amounts cannot readily exist obtained through dietary means, these effects should be considered pharmacologic and not nutritional in nature.
Recent information from genomic screening experiments in mice and humans advise that there is some other reason that results from mouse feeding studies with n–three PUFA too every bit other fat sources may have led to findings that were non predictive of responses in humans (64). In this report, the authors compared the temporal changes in the expression of thousands of genes from blood leukocytes isolated from humans or mice later 3 forms of serious trauma: burns, endotoxemia, and blunt injury. The genomic responses in circulating man leukocytes to these diverse forms of trauma were surprisingly similar. Yet, among the genes that were changed significantly in humans, the mouse orthologs failed to reflect similar changes (R ii between 0.0 and 0.i; run across Figure 5 ). These data suggest that mouse models poorly reflect the physiologic responses seen in humans to systemic inflammatory challenges. In fact, similar conclusions were drawn in a 2007 commodity, in which the clinical outcomes (e.k., circulating cytokines, leukopenia, fever, changes in respiration) associated with sepsis in humans and the diverse "relevant" mouse models were compared (65). Researchers should therefore practise caution when relying solely on mouse models for investigating the impact of dietary fats on inflammatory responses/condition in humans.
Comparison of the genomic response in circulating leukocytes to astringent acute inflammation from 6 distinct causes in human and murine models. GEO was queried for studies in the white blood cells of astringent acute inflammatory diseases (i.e., burns, endotoxemia, trauma, sepsis, ARDS, and infection) in humans and mice. The fold-modify of each factor measured was calculated between patients and controls in a homo report or between treated and control groups in a murine model study; and for a time-grade data set up, the maximum fold-alter was calculated. The gene response in each data set was then compared with the 5554 genes that were significantly changed in human being trauma, burns, and endotoxemia. Shown are correlations (x axis) and directionality (y axis) of gene response from the resulting multiple published information sets in GEO compared with human fire injury. ARDS, acute respiratory distress syndrome; GEO, Gene Expression Omnibus. Reproduced from reference 64 with permission.
Conclusions
Dietary fats have a major impact on human wellness. A growing body of bear witness suggests that inflammatory status should be included as ane of the characteristics for which dietary fats are evaluated relative to their affect on human health. At this time, information technology is uncertain how dietary fats might bear upon inflammatory status, but current show suggests that the gut microbiome is of import in this regard. Studies should account for the possibility that fats tin have both acute as well as chronic effects on host inflammatory responses. Whereas cell culture and creature models play an important role in biomedical research, limitations inherent in these models suggest that data from homo clinical trials will continue to accept primacy in setting dietary recommendations for fats and FAs. In lite of the lack of consensus regarding which biomarker is best for monitoring inflammatory condition, it is recommended that as many inflammation biomarkers be measured every bit feasible and that studies be appropriately powered in recognition of the highly variable nature of these biomarkers.
Acknowledgments
The sole writer had responsibleness for all parts of the manuscript.
Footnotes
4Abbreviations used: AA, arachidonic acid; ALA, α-linolenic acid; CRP, C-reactive protein; GPR120, M protein–coupled receptor 120; LA, linoleic acrid; LTBfour, leukotriene B4; MF, milk fat; TLR, toll-like receptor.
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