Saturated Fat: Part of a Healthy Diet - PDF Document

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  1. Current Nutrition Reports https://doi.org/10.1007/s13668-018-0238-x GASTROENTEROLOGY, CRITICAL CARE, AND LIFESTYLE MEDICINE (SA MCCLAVE, SECTION EDITOR) Saturated Fat: Part of a Healthy Diet Victoria M. Gershuni1,2 #Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Purpose of Review Despite the American public following recommendations to decrease absolute dietary fat intake and specif- icallydecreasesaturated fat intake,wehaveseena dramaticriseoverthe past40yearsinthe ratesofnon-communicablediseases associated with obesity and overweight, namely cardiovascular disease. The development of the diet-heart hypothesis in the mid twentiethcenturyledtofaultybutlong-heldbeliefsthatdietaryintakeofsaturatedfatledtoheartdisease.Saturatedfatcanleadto increased LDL cholesterol levels, and elevated plasma cholesterol levels have been shown to be a risk factor for cardiovascular disease; however, the correlative nature of their association does not assign causation. Recent Findings Advances in understanding the role of various lipoprotein particles and their atherogenic risk have been helpful for understanding how different dietary components may impact CVD risk. Numerous meta-analyses and system- atic reviews of both the historical and current literature reveals that the diet-heart hypothesis was not, and still is not, supported by the evidence. There appears to be no consistent benefit to all-cause or CVD mortality from the reduction of dietary saturated fat. Further, saturated fat has been shown in some cases to have an inverse relationship with obesity-related type 2 diabetes. Summary Rather than focus on a single nutrient, the overall diet quality and elimination of processed foods, including simple carbohydrates,wouldlikelydomoretoimproveCVDandoverallhealth.ItisinthebestinterestoftheAmericanpublictoclarify dietary guidelines to recognize that dietary saturated fat is not the villain we once thought it was. Keywords Saturatedfat.SFA.Fattyacids.Dietaryfat.Triglycerides.PUFA.LDLcholesterol.Diet.Cardiovasculardisease. CVD.Atherosclerosis.Diet-hearthypothesis.Dietaryguidelines Introduction diseases. By the 1980s, the diet-heart hypothesis aka “lipid hypothesis”—the assumption ofa causalrelationshipbetween dietary fat consumption and coronary heart disease (CHD)— was widely accepted by the nutritional and medical commu- nity as dogma [1]. However, this hypothesis has not been proven to be correct despite its widespread acceptance. Thelow-fatfadwithrecommendationstolimitsaturatedfat to minimal levels has been the result of multiple influences. These include the relationship between the U.S. government and dietary guidelines, ecological and epidemiological studies investigating the relationship between diet and chronic dis- ease, and most importantly, a misunderstanding of the bio- chemistry of different types of fat and their ultimate impact on human physiology. Dietary fat is an essential nutrient that is a component of every cell in the human body; the human brain is made up of approximately 60% fat. Fatty acids are essential to all body tissues as components of phospholipid bilayers that make up With the rise of obesity, overweight, and chronic disease in Western countries, there has been a flurry of interest in under- standing both why we get fat and how we can deal with it. Over the last half century, there have been various dietary strategies promoted to combat obesity and its associated Thisarticleispartofthe TopicalCollectiononGastroenterology, Critical Care, and Lifestyle Medicine * Victoria M. Gershuni Victoria.Gershuni@uphs.upenn.edu 1 Department of Surgery, Hospital of the University of Pennsylvania, 3400 Spruce Street, 4 Maloney, Philadelphia, PA 19104, USA 2 Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

  2. info@ernaehrungsmediziner.de Von: Gesendet: An: Cc: Betreff: Nicolai Worm <Nicolai.Worm@t-online.de> Mittwoch, 15. August 2018 16:04 kmichels@hsph.harvard.edu tumorepidemiologie@uniklinik-freiburg.de Superfood, Vitamin D und Kokosöl https://www.youtube.com/watch?v=Mnc_aoN7lMM Sehr geehrte Frau Prof. Michels, Ihren Aussagen zu Superfood und Vitamin D kann ich gut beistimmen. Hingegen haben mich Ihre Aussagen zu gesättigten Fettsäuren, Schweineschmalz und Kokosöl regelrecht erschreckt. Zum Beispiel besteht ja Schweineschmalz überwiegend aus ungesättigten Fettsäuren, wie man jeder Nahrungsmitteltabelle entnehmen kann. Deswegen ist es bei Raumtemperatur auch nicht fest, wie von ihnen postuliert, sondern pastös. Oder: Gesättigte Fettsäuren sind in Dutzenden Kohortenstudien ohne Risiko für kardiovaskuläre Erkrankungen ausgewiesen worden. Meta-Analysen dieser Studien haben das bestätigt. Anbei die neueste Übersichtsarbeit zum Thema, die auch die Meta-Analysen auflistet. Würden Sie mir deshalb bitte Belege für Ihre Aussagen schicken, dass Kokosöl bzw. gesättigte Fette „die Koronargefäße verstopfen“ und Atherosklerose fördern würden. Vielen Dank und Grüße, Nicolai Worm _________________ Dr. Nicolai Worm Geibelstrasse 9 D-81679 München Fon: +49-89-41929387 Fax: +49-89-41929432 WebsiteFacebookTwitter 1

  3. Curr Nutr Rep rigid molecules that are able to pack tightly next to each other to form a solid. Unsaturated fats, however, are liquid at room temp due to double bonds that interfere with the stacking of the lipid molecules. Monounsaturated fatty acids (MUFA) haveasingledoublebond,whichproducesakinkinthechain. This bend then produces a dietary fat that is liquid at room temperature but solid when chilled (i.e., olive oil, avocado oil). Multiple double bonds are found in polyunsaturated fatty acids (PUFA, i.e., soybean, corn, fish, flaxseed, and most “vegetable”oils).Theseareliquidatroomtemperatureaswell as when chilled due to the multiple kinks along the length of the chain that interfere with the molecules packing tightly. Further classification of PUFA is dependent on the location of the double bond that impacts oxidation and metabolism of the fatty acid. The bonds are identified by their distance from theendofthechainandcanbereferredtoasomega-3,omega- 6, omega-7, or omega-9 fatty acids. These variations of PUFAs have distinct metabolites that have reciprocal impacts on inflammation and metabolism (i.e., omega-3 fatty acids found in fish oil are considered anti-inflammatory, whereas omega-6 fatty acids like those in soybean oil are considered pro-inflammatory). It isimportant tonotethatthe industrialization ofvegetable oils also brought with it the creation of trans-fatty acids. This process of hydrogenation takesan unsaturated fat and forcibly introduces hydrogen atoms into the double bond to remove the kink present in the carbon chain. By rearranging the ori- entation around the double bond (change from cis to trans position), trans fats are solid at room temperature and have a long shelf life, which ultimately led to their use in the proc- essedfoodindustry. Industriallyproducedtrans fatshavebeen shown to be unequivocally detrimental to human health and are not recommended for consumption [10••]. This topic is beyond the scope of this review. cell membranes. They are used as a source of fuel, especially within the myocardium. Rather than avoiding dietary fat, we need to understand the role of each type and how it can be a part of a healthy diet. Not all fat is created equal, and the chemical structure of the fat molecule will dictate how it is processed by the human body. The big question this review seeks to answer is whether saturatedfatcanbeapartofahealthydiet.Theshortanswerto this question is yes. The long answer is that it is complicated. This review will attempt to clarify the history and background of our current dietary guidelines and describe the up-to-date scientific literature that exists on the relationship between di- etary saturated fat (SFA) and human health. Understanding Dietary Fat: What Is Saturated Fat? Fatty Acids and Triglycerides The majority of dietary fat is composed of triglycerides (aka triacylglycerides), the storage form offatty acids that make up 95% of dietary fat. Triglycerides are composed of three differ- ent fatty acids attached to a glycerol backbone and contain the primarysourceofenergyandcaloriesderivedfromdietaryfat. Fatty acids are the simplest class of lipid and structurally are composed of a hydrocarbon chain that terminates in a carbox- ylic acid group. This allows them to have different polarity on either end and affects their ability to mix with water (solubil- ity). Different properties are also conferred to fatty acids de- pendent on carbon chain length (4–24 carbons) and degree of saturation (location and number of double bonds). These structural differences contribute to variable absorption, trans- port, and destination [2, 3]. Short chain fatty acids (SCFA, two to six carbons)—which are derived from fiber and non-digestible polysaccharides— are not only used as fuel sources for the cells of the colon but also function as signaling molecules that can impact gene expression [4–9]. The majority of dietary fat is in the form of either medium chain fatty acids (MCFA), which are com- posed of eight to 12 carbons, or long chain fatty acids (LCFA) that have 14 to 20+ carbons. The length of the carbon chain dictates whether the fat will be absorbed directly into the bloodstream via the portal circulation (i.e., SCFA and MCFA) or if it will be packaged by bile acids into micelles in the gut lumen and delivered via the lymphatics in the form of chylomicrons (LCFA). Thedegreeofsaturationdetermineswhetherafatissolidor liquidatroomtemperature.Agreater numberofdoublebonds in the carbon chain confer more flexibility and thus fluidity to thefattyacid,whichcanimpactphysiologyasfattyacidsform cell membrane lipid bilayers. In saturated fats, there are no double bonds, so the fatty acids are straight, compact, and Biological Consequences of Dietary Fats Dietary fat is a fundamental component of a healthy diet and provides energy, a source of essential fatty acids (linoleic and alpha-linolenicfattyacids),andisnecessaryfortheabsorption offat-soluble vitamins(A, D,E, K). Dietary fatsare important for gastric emptying, digestion, and satiety. They are also principal components of hormones, including steroid and sex hormones. Their metabolic and overall health effect may not be adequately predicted by the general classification of saturated versus unsaturated fatty acids. There is evidence to suggest that chain length of individual fatty acids, processing methods, dietary source, and the dietary pattern associated with consuming fat may be more helpful in predicting a phys- iologic effect [11–14]. The triglycerides found in food can be composed of multi- ple types of fatty acids. Dietary saturated fat is often found in animal products—milk (varies by species), cheese, butter,

  4. Curr Nutr Rep have a differential effect on the development of obesity. In a study looking at the development of diet-induced obesity (DIO) in mice fed high-fat diets that compared cholesterol- rich lard versus cholesterol-free palm oil, researchers found that germ-free mice were resistant to DIO when fed a lard- based high-fat diet. However, germ-free mice fed an iso- caloricpalm-oil-baseddietdeveloped obesity[16].Themech- anisms behind these differences point to the ability for differ- ent fatty acids to significantly impact gut microbial species and bile acid metabolism in a way that affects crosstalk be- tweenthegutmicrobiotaandhostmetabolism.Itisimperative thatweunderstandthatthedietweeatimpactsboththehuman and the microbes that live within us [9]. Importantly, the human body is capable of endogenous syn- thesis of fatty acids, specifically PA. Despite the villainization of dietary saturated fat, it is necessary to recognize that PA has crucial physiologic activities and, if not provided by the diet, it will be synthesized by the body via de novo lipogenesis (DNL) [17]. More important than the absolute intake of PA is the balance of a certain ratio with unsaturated fatty acids, specifi- cally omega 6 and omega 3 PUFAs. Factors such as positive energy balance, sedentary lifestyle, and excessive intake of car- bohydrates (in particular mono and disaccharides), and a sed- entary lifestyle contribute to dysregulation of the mechanisms that maintain a steady state of PA concentration. This homeo- static disruption can lead to over accumulation of tissue PA that results in altered lipid profiles, elevated blood sugar, body fat accumulation, and increased inflammatory signaling via toll- likereceptor4[17].Ratherthanfocusoneliminatingthissingle nutrient—PAfoundinSFA—weneedtofocusonthetotalityof our diet, including the content of other macronutrients and the quality of the food we consume. As mentioned earlier, SCFA and MCFA are absorbed di- rectly into the bloodstream and go to the liver via the portal vein for direct utilization by the hepatocytes. LCFA, on the other hand, are solubilized by bile acids in the intestine before they are packaged into micelles and absorbed by the cells lining the intestine. Once there, they are repackaged into chy- lomicrons and sent through the lymphatic system before reaching the blood stream and eventually making their way to the liver. They then need to be unpackaged to be metabo- lized by the liver. If there is a surplus, they are stored—in the liver, adipose, and muscle. The breakdown of these LCFA occurs via beta-oxidation, which is dependent on lipoprotein lipase (LPL), an insulin-sensitive hormone. When insulin levels are high, LPL is inhibited and effectively turned off, so LCFA are not able to be broken down and instead get stored. After eating a sugar heavy meal (i.e., anything with processed food), we get an insulin spike that inhibits our abil- ity to break down fat for fuel. Further, any excess carbohy- drate is converted to fat that is also stored. This relationship underscores the importance of context when talking about dietary macronutrients. eggs, meat, and fish—and inplant foods as well, likecoconut, cacao, cashews, palm, and palm kernel. Despite food items containing varying combinations and different proportions, nutrition labels are unable to discriminate between particular fatty acids. The saturated fat found in meat, eggs, cacao, and nuts is primarily composed of triglycerides containing palmitic and stearic acids. Over 90% of fatty acids found in the standard American diet are either palmitic acid (C16:0), stearic acid(C18:0), oleic acid(C18:1),orlinoleicacid(18:2). Linoleic acid is the predominant fatty acid found in omega 6 PUFA,representingtheshifttowardincreasedconsumptionof vegetable oils in the American diet in order to decrease intake of SFA. Evenwithinsimilar fat sources,i.e., conventionalgrain-fed beef vs. pastured grass-fed beef [15], there can be substantial variation in the fatty acid content. The type offatty acid found inmeatfromanimalsisdependentonwhattheanimalate,soa grass-fed cow will have significantly greater omega-3 PUFA content than conventionally raised, grain-fed cows that have higher amounts of omega-6 PUFA. The quality and fatty acid makeup of the dietary fat we choose to consume has far- reaching implications. Research over the past three decades has revealed that grain-fed cattle have fattier meat, fewer micronutrients and minerals (i.e., beta-carotene, conjugated linoleicacid), a differentfatty acidprofile (less omega 3,more omega 6), and less antioxidant potential than grass-fed cows [15]. Similarly, the dairy produced by cattle has a different fatty acid profile. For example, butter contains large amounts of the SCFA butyrate (C4:0), in addition to 3, 11, and 29% of lauric, myristic, and palmitic acids, respectively. Thus, when incorporating these foods into our diets, we must also remember that the source of our SFA matters. In grass-fed beef, there are greater amounts of cholesterol neutral stearic acid (C18:0) and decreased levels of myristic acid (C14:0) and palmitic acid (C16:0), which have been shown to raise LDL-C [15]. The saturated fatty acids lauric acid (C12:0) and myristic acid (C14:0) have a greater choles- terol raising effect than palmitic acid (C16:0). A caveat to lauric acid’s cholesterol raising effects is that it is predomi- nantly a rise in HDL-C cholesterol, which has been shown to be more protective against CVD. Stearic acid (C18:0), on the other hand, has a neutral effect on total serum cholesterol and does not impact LDL-C or HDL-C. This may be due to con- version of stearic acid to oleate, which is similar to the mono- unsaturated oleic acid. Within plant-sourced saturated fat, there is also consider- able variability in the fatty acid composition. Despite being from the same plant, coconut oil is composed of primarily MCFA (47% lauric acid) with a smaller proportion from LCFA (18% myristic acid and only 9% palmitic acid), where- as palm kernel oil contains similar MCFA (48%) but only negligible myristic acid (1%) and dramatically more palmitic acid (48%). Evidence suggests that palmitic acid (PA) may

  5. Curr Nutr Rep Understanding Disease Risk: What Is Atherogenic Dyslipidemia? effect. However, HDL-C as a metric is measuring a complex heterogeneous mix of lipoprotein particles and may not be adequately representing the various athero-protective, antiox- idant, anti-inflammatory, and cholesterol efflux properties of the underlying lipoprotein particles [26–28]. Individuals with the same total cholesterol levels can have vastly different lipoprotein particle patterns that con- fer different disease risk. Atherogenic dyslipidemia—the triad of elevated small, dense LDL-C, decreased HDL-C, and increased triglycerides—is a risk factor for CVD and myocardial infarction. Not surprisingly, this atherogenic dyslipidemia pattern is a typical feature of obesity, meta- bolic syndrome, and type 2 diabetes [18]. As evidence of the complexity of this relationship, 80% of participants in the Framingham study who developed CAD had the same total cholesterol as those that did not develop CAD [29]. Recent dietary studies have demonstrated that total or sat- urated dietary fat has minimal effect on lipoprotein profile; however, high carbohydrate diets have been shown to promote the development of atherogenic dyslipidemia [18, 30–32]. Cardiovascular disease risk is traditionally assessed with a fasting lipoprotein profile that measures total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density li- poprotein (LDL-C),and triglycerides(TG).Cholesteroliscar- ried throughout the body in multiple lipoprotein particles that vary by size and amount of cholesterol they carry; these par- ticle characteristics impact the way they are absorbed and utilized by cells. LDL-C is composed of a heterogeneous group of particles thatarecharacterizedbasedonsize(largerisbetterthansmall- er) and the density of cholesterol within the particle (particles with less cholesterol are more buoyant, which is good). At least four different categories of LDL-C exist that are subdivided further into eight sub-fractions [18]. One of the simpler classifications of LDL-C is into large, buoyant type A particles and small, dense type B particles. The interaction between diet and lipoprotein particle size and density is a complex topic that continues to evolve. Multiple studies suggest that the small, dense LDL-C par- ticles possess greater atherogenic risk and are more likely to promote development of CVD [19–23]. This may be due to higher potential for oxidation of these small LDL-C particles that ultimately promotes inflammation and atherosclerosis. Dietary studies have demonstrated that saturated fat intake impacts large, buoyant type A particles, whereas small, dense type B particles are impacted by carbohydrate intake [18]. Without categorizing by particle size, LDL-C is a suboptimal biomarker for understanding potential CVD risk in a popula- tion or for evaluating and targeting dietary interventions. Based on epidemiological associations with cardiovascular disease, higher levels of HDL-C are considered to have a protective effect against cardiovasculardisease and act bycar- rying cholesterol from peripheral tissues back to the liver for metabolism. There are two to three different sub-fractions of HDL-C that confer different behaviors. Evidence shows that the HDL-C to TG ratio is far more predictive of CVD events than LDL-C. The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) trial, a randomized, double-blindclinicaltrialattemptingtoalterlipidprofileswith extended release niacinand statins inpatientswithestablished cardiovascular disease, found that fasting lipoprotein profiles atbaselinewerenotpredictiveofclinicalCVDeventsineither group [24]. Despite increasing levels of HDL-C in the inter- vention arm, they did not see a respective decrease in CVD risk, which goes against traditional views of HDL-C having a causal relationship with CVD [25]. In epidemiological stud- ies, HDL-C has been shown to be inversely related to CVD risk, which suggests that it may have an athero-protective Understanding the History of Current Dietary Guidelines: What Is a Healthy Diet? The original USDA dietary guidelines were introduced in 1894 followed by the first USDA food guide in 1916. Early in the twentieth century, the main focus of dietary guidelines was toavoid vitamin deficienciesand malnutrition. Following the Great Depression and close of World War II, better so- cioeconomic, sanitation, and nutrition conditions led to an epidemiologic transition. As chronic diseases became more prevalent, a paradigm shift in nutritional recommenda- tions was promoted based on a growing interest in the relationship between diet and CVD. By the 1940s, car- diovascular disease (CVD) had become the leading cause of mortality in the USAwith little known about its natural history, prevention, or treatment. After President Roosevelt’s death secondary to CVD, President Truman signed the National Heart Act to devote resources to un- derstanding the nationwide epidemic. In 1948, the Framingham Heart Study was initiated to investigate the relationship between cardiac health and environmen- tal and lifestyle factors. The first reference to this notion was in the 1957 American Heart Association guidelines that said, “Diet may play an important role in the patho- genesis of atherosclerosis” [33, 34]. Early ecological, epidemiological,and short-term interven- tion studies were conducted to evaluate the link between diet and non-communicable chronic diseases. Ancel Keys, Frederick Stare, and Mark Hegsted were at the helm of the ship promoting the connection between dietary fat and heart

  6. Curr Nutr Rep category. After all, pizza, potato chips, biscuits, and candy are not only high in SFA but also contain plenty of simple sugars, carbs, and preservatives [41]. Saturated fat in the con- text of a highly processed diet full of simple sugars and proc- essed starches (i.e., a Western diet) is not a healthy diet. In the USA, saturated fats makeup approximately 10% of calories in the standard high sugar, highly processed diet. Issued, and presumably updated, every 5 years, the US Dietary Guidelines for Americans impact the nutrition recom- mendations and diet for the US population. The guidelines dictate nutrition education, food labeling, food stamp pro- grams and publicassistance, and government-funded research programs at the National Institutes of Health (NIH). These guidelines extend beyond the US and guide most Western nations as they adopt similar nutrition policy globally. As brilliantly outlined by Teicholz in her critique of the 2015 dietary guidelines, the committee did not adequately surveil thescientificliteraturewhenpreparingthenewestupdate[42]. Rather, it relied primarily on recommendations from profes- sionalassociations, including the AmericanHeart Association (AHA) and the American College of Cardiology (ACC), and did not include systematic criteria for rigorous review of the updated literature. On the topic of saturated fats, specifically, the committee failed to conduct a formal review of newly published literature over the prior 5 years. Multiple meta- analyses and systematic reviews [43–45] that did not support the association between saturated fats and heart disease have been published since the 2010 dietary guidelines, but these were not reviewed by the committee. While there was move- ment away from the original recommendation of the 30% upper limit on dietary fat intake, the SFA guideline did not change, and recommendation to consume <10% of daily cal- ories from SFA remains [46]. disease. Contemporaneously, John Yudkin had identified sug- ar as a major contributor to CAD, high triglycerides, cancer, and dental caries [35]. Keys and colleagues began the Seven Countries’ study [36], which looked at the epidemiological associationbetweensaturatedfatintakeandheartdiseasemor- talityinover12,000menfromsevencountries.Unfortunately, while they did identify a potential association, their method- ology was limited by data collection issues, and they did not control for all confounders like smoking, sugar intake, or ex- ercise. Keys acknowledged these limitations by saying, “There is no guaranty that the main points of this discussion are actually about arteriosclerosis or the particular variety la- beled atherosclerosis” [37]. Ultimately, this correlative rela- tionshipbecamefodderfor muchofthe supportofeliminating fat from our diet. Based on the work by Keys, in 1977, the US Senate Committee led by Senator George McGovern released Dietary Goals for the United States, which concluded that “the overconsumption of foods high in fat, generally, and sat- urated fat in particular, as well as cholesterol, refined and processed sugars, salt and/or alcohol has been associated with the development of one or more of six to ten leading causes of death: heart disease, some cancers, stroke and hypertension, diabetes, arteriosclerosis and cirrhosis of the liver.” In this report, they made seven specific recommendations, including reduction of overall fat consumption from 40 to 30% and reduction of saturated fat from 16 to 10% [38]. Despite this low-fat, low cholesterol diet now being accepted, there was opposition within the science community. In 1980, the US National Academy of Sciences Food and Nutrition Board ar- gued that there was insufficient evidence to support limiting total fat, saturated fat, or dietary cholesterol in our dietary guidelines [35, 39]. In 1988, the Surgeon General’s Report supported the no- tion that in order to decrease consumption of “bad fat,” the public should decrease consumption of all fat. With this, the “low-fat” craze was started, heralding in the creation of the low-fat and non-fat food market. Despite the expansion of low- and non-fat food products and an overall decrease in fat consumption, there has been a parallel surge in overweight and obesity. In the last 30 years, Americans have decreased their fat intake by 10%, but the obesity rate has doubled [40]. By focusing on limiting a single dietary macronutrient, the food guidelines failed to underscore the importance of a bal- anced intake of calories and the contextual importance of di- etary fat within a well-formulated diet [33]. Interestingly, however, the official listed sources of saturat- ed fat are essentially lists of processed foods that include baked goods, candies/sweets, desserts, snacks, and packaged meals. Thus, it is even more unclear whether the ecological and epidemiological associations seen between SFA intake and CVD are due to the actual SFA content or secondary to the processed nature of the foods that are listed under this Understanding the Research: What Evidence Exists? The existence of an ecological association between CHD and elevated serum cholesterol does not translate to causation. Multiple large trials involving interventions to reduce total cholesterol have not been able to show a reduction in total mortality [1, 47–49]. The Honolulu Heart Study [50] contra- dicts this dictum further by demonstrating increased all-cause mortality among participants with lowered cholesterol levels. In a 30-year follow-up of the Framingham Heart Study, re- searchers found a direct association between decreased cho- lesterol levels over the first half of the study and higher mor- tality during the second half of the study [49]. Other studies found no correlation between dietary fat, serum cholesterol, and CHD mortality [51–53]. The traditional diet-heart hypothesis predicts that by reduc- ing dietary intake of SFA, the compensatory decrease in serum

  7. Curr Nutr Rep According to the few clinical studies that have looked at SFA and risk factors, the relationship between SFA intake and CVD risk varies depending on chain length. The Nurse’s Health Study (NHS) was unable to demonstrate an increased risk of coronary heart disease with consumption of short- to medium-chain SFA (p>0.6). However, when comparing the highest intake to lowest intake of long chain SFA, there was a slightlyincreasedriskofCHDamongthehighestintakegroup after adjustment (RR 1.14, 95% CI 0.93, 1.39, p=0.03) [57]. In the Women’s Health Initiative Dietary Modification (WHI DM) trial, which compared decreased saturated fat in- take with controls over a mean of 8.1 years in a large, con- trolled clinical trial of over 48,800 women, there were no observed statistically significant differences associated with lower saturated fat intake compared to usual diet in terms of lipoprotein profiles (LDL-C or HDL-C particle size or num- ber), metabolic syndrome, incidence of fatal or non-fatal car- diac events, stroke, or CVD [58, 59]. Furthermore, the PREDIMED trial looked at a low-fat diet compared to a Mediterranean diet supplemented with olive oil or nuts, and found approximately 30% decrease in cardiovascular events over 4.8 years despite increased fat intake [60, 61]. In a landmark systematic review and meta-analysis pub- lished in 2015, de Souza et al. corroborated previous system- atic reviews that found no discernible association between SFAintakeandall-causemortality,CVD[62],CHDincidence [43, 62–64] or mortality[43, 62, 63], ischemic stroke [43], or type 2 diabetes in healthy adults [10••]. Dietary fatty acids were further exonerated in a different systematic review, me- ta-analysis, and meta-regression that assessed the role of die- tary fat in the secondary prevention of CHD and found that there was no benefit from reduction of total dietary fat or SFA in decreasing myocardial infarction, CVD, or all-cause mor- tality. Further, recommendingPUFA toreplace SFAconferred no improvement in risk reduction [65]. In a 2017 meta- analysis of randomized controlled trials, Hamley et al. found that after controlling for confounders, replacing SFA with mostly omega 6 PUFA is unlikely to reduce CHD events, CHD mortality, or total mortality. Harcombe and colleagues published multiple reviews, including currently available RCT evidence (over 62,000 participants), that do not support the current dietary guidelines to restrict dietary fat. Again, despite reductions in cholesterol, there were no significant differences in CHD or all-cause mortality [41, 66, 67, 68••]. These findings reinforced the conclusions of multiple other recent systematic reviews that have challenged the traditional diet-heart hypothesis (see Table 1) [43, 70, 71, 74–77]. In a randomized trial conducted from June to July 2017, healthy adults between 50 and 75 years old were placed on one of three different diets that differed by fat content. Participants were instructed to consume 50 g of either extra virgin coconut oil (SFA), olive oil (MUFA), or unsalted butter (SFA) daily for 4 weeks in addition to their usual diet. When cholesterol would translate to a lower risk of CVD and death. However, upon re-analysis of data from the Minnesota Coronary Experiment [54], a long-term, double blind RCT that drastically decreased SFA in favor of “heart healthy” linoleic acid (omega 6 PUFA from corn oil), Ramsden and colleagues revealed that despite an average 30 g/dL decrease in serum cholesterol, the risk and incidence of all-cause mortality in- creased by 22% in the PUFA intervention group (based on a Cox model adjusted for baseline serum cholesterol, age, sex, adherence to diet, BMI, and SBP). For those who started the studyaged>65,theyhada 35%higherriskofdeathassociated with a 30 mg/dL decrease in serum cholesterol. Even more intriguing,thisre-evaluationofthedatafromthistrialrecovered autopsy results, which enabled them to assess incidence of ath- erosclerosis and myocardial infarction. In the PUFA interven- tion group, 41% of participants had at least one MI vs. only 22%oftheSFAcontrolgroup.Likewise,theinterventiongroup did not have less coronary or aortic atherosclerosis. The as- sumption that dietary cholesterol and saturated fats accumulate in the arteries is in opposition with the actual composition of arterial plaques. Felton et al. found that the arterial plaques within the aorta are primarily composed of unsaturated fats and concluded that this implies “a direct influence of dietary polyunsaturated fatty acids and not of saturated fats on aortic plaque formation and suggest that current trends favoring in- creased intake of polyunsaturated fatty acids should be reconsidered” [55]. This may have something to do with the pro-inflammatory mediators produced by omega 6 PUFA. Ramsden et al. also evaluated recovered unpublished data from the Sydney Diet Heart Study [56], a single-blinded, ran- domized controlled trial from 1966 to 73. Again, they found that the advice to replace SFAwith omega 6 PUFA for coro- nary heart disease reduction may be misguided. In this cohort, theyfoundincreasingratesofdeathfromallcauses,CHD,and CVD when SFAwas replaced by linoleic acid. In conjunction with the re-analysis of both sets of primary data, the authors performed systematic reviews and meta-analyses and failed to find significant beneficial cardiovascular impact for use of omega 6 PUFA in place of SFA [56]. Likewise, on meta-anal- ysis, they found that a mean decrease in serum cholesterol (7.8–13.8%) was not associated with decreased incidence of MI or any benefit on mortality from CHD [54]. The results of these meta-analyses of previously unpub- lished data challenge the proposition that decreased SFA lowers plasma cholesterol levels and thereby decreases risk of CAD. Despite lowering plasma lipid levels, there was no clinical benefit to the participants but rather increased risk of CAD [54]. Of course, it is prudent to remember that these detrimentaleffectsmaybeduetoincreasedlinoleicacid(ome- ga 6 PUFA) asopposed todecreasingSFA.But,in the context of dietary recommendations to decrease SFA in favor of linoleicacid-richvegetableoils(omega6PUFA),theseresults are striking and relevant.

  8. Curr Nutr Rep Table 1 Significant systematic reviews and meta-analyses on saturated fat consumption (2008–2018) Author/year Title Main findings Hamley, 2017 [69•]** The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials After adequately controlling for confounders, the available evidence from RCTs suggest that replacing SFAwith mostly n-6 PUFA is unlikely to reduce CHD events, CHD mortality or total mortality Currently available RCTevidence (62,421 participants) does not support the current dietary guidelines to restrict dietary fat. Despitereductionsinmeanserumcholesterollevels,therewere no significant differences in CHD or all-cause mortality No significant difference for total mortality or cardiovascular mortality secondary to modified dietary fat intake, reduced dietary fat intake, or combined modified and reduced dietary fat intake. Small suggestion of benefit for CVD event risk in modifying dietary fat intake toward PUFA over SFA, however unclear what PUFAwould be beneficial No differences in all-cause mortality and non-significant differences in CHD mortality resulted from the dietary interventions(decreaseintotalfat,saturated fat,orreplacement with vegetable oil). Intervention groups had significant reductions in mean serum cholesterol levels; however, this did not resultin significantdifferences in CHD orall-cause mortality. Original government dietary fat recommendations (US in 1977 and UK in 1983) were untested in any RCT prior to being introduced No discernable association was found between SFA intake and all-cause mortality, CVD, CHD incidence or mortality [43, 62, 63], ischemic stroke, or type 2 diabetes in healthy adults No evidence for benefit of reduced/modified fat diets with regard to all-cause mortality, CVD mortality, or CVD events in the secondarypreventionof CHDbasedonevidencefromRCTsin patients with established CHD No association of dietary SFA intake, nor circulating SFA, with CHD Failed to find significant beneficial cardiovascular impact for use ofomega 6 PUFA in place of SFA.Substitutingdietary linoleic acid (PUFA) in place of SFA increased rates of death from all causes, CHD, and CVD Differential impact of SFA on CVD risk depending on source: higher dairy SFA associated with lower CVD risk, higher intake of meat SFA associated with greater CVD risk Results and conclusions about saturated fat intake in relation to cardiovascular disease, from leading advisory committees, do not reflect the available scientific literature In a systematic review of RCTs of disease endpoints for cardiometabolic effects of SFA consumption in humans, replacing SFAwith PUFA modestly lowered CHD risk (10% RR for 5% energy substitution), whereas replacing SFAwith carbohydrate had no benefit and replacing SFAwith monounsaturated fat had uncertain effects Evidence from RCTs suggests that replacing SFAwith PUFAs reduced CHD events but did not reduce mortality Harcombe, 2016 [68••]** Evidence from randomised controlled trials does not support current dietary fat guidelines: a systematic review and meta-analysis Hooper, 2015 [70] Reduction in saturated fat intake for cardiovascular disease (Cochrane Database Systematic Review) Harcombe, 2015 [71]* Evidence from randomised controlled trials did not support the introduction of dietary fat guidelines in 1977 and 1983: a systematic review and meta-analysis de Souza, 2015 [10••]** Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies Schwingshackl, 2014 [65] Dietary fatty acids in the secondary prevention of coronary heart disease: a systematic review, meta-analysis and meta-regression Chowdhury, 2014 [62] Ramsden, 2013 [56] Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis Dietary intake of saturated fat by food source and incident cardiovascular disease: the Multi-Ethnic Study of Atherosclerosis Saturated fat and cardiovascular disease: the discrepancy between the scientific literature and dietary advice de Oliveira Otto, 2012 [72] Hoenselaar, 2011 [73] Micha, 2010 [74] Saturated fat and cardiometabolic risk factors, coronary heart disease, stroke, and diabetes: a fresh look at the evidence Mozaffarian, 2010 Effectsoncoronaryheartdiseaseofincreasingpolyunsaturatedfat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials Meta-analysis of prospective cohort studies evaluating the association of saturated fat with cardiovascular disease Fat and coronary heart disease: summary of evidence from prospective cohort and randomised controlled trials Siri-Tarino, 2010 [43] Skeaff, 2009 [63] No significant association between dietary saturated fat and increased risk of CHD or CVD “The available evidence from cohort and randomised controlled trials is unsatisfactory and unreliable to make judgment about and substantiate the effects of dietary fat on risk of CHD”

  9. Curr Nutr Rep assessing for LDL-C (primary outcome), butter was found to significantlyincreaseLDL-Ccomparedtococonutoil(+0.42, p<0.0001) or olive oil (+0.38, p<0.0001). No difference was found between the saturated coconut oil and the mono- unsaturated olive oil. Further, coconut oil was found to signif- icantly increase beneficial HDL compared with both butter and olive oil (+0.18 and +0.16, respectively). There were no significant changes in weight, blood sugar, or blood pres- sure between the groups. This study highlighted the impor- tance of assessing fatty acid profiles and processing methods in determining differential effects of saturated fatty acids [11, 78]. Despite containing approximately 90% saturated fat, co- conut oil had more beneficial effects than butter (which has approximately 50–66% saturated fat). This may be secondary to a different fatty acid profile; coconut oil is composed of 48% lauric acidwithmyristic acid[79, 80].Conversely, butter is composed of 40% palmitic and stearic acids. Interestingly, within butter, the LCFA palmitic and stearic acid may have opposing physiological effects. In a study looking at healthy males, the consumption of 19 g/day dietary stearic acid com- pared to dietary palmitic acid for 4 weeks was associated with improved thrombogenic and atherogenic risk factors, includ- ing plasma lipid concentrations [81]. Mozaffarian and colleagues performed a systematic review and meta-analysis looking at the association of butter con- sumption with all-cause mortality, CVD, and diabetes in the general population. Their analysis included 9 publications with 15 country-specific cohorts (over 636,000 participants) and included over 6.5 million person-years in follow-up with over 28,000 deaths. They found a weak and minimal associ- ation of butter with all-cause mortality (RR=1.01, 95%CI 1.00, 1.03, p=0.045), no significant association with any car- diovascular disease, coronary heart disease, or stroke. They did, however, find a modest inverse association with SFA consumption and the incidence of type 2 diabetes (RR = 0.96, 95%CI 0.93, 0.99, p=0.021) [82]. Similarly, the WHI DM failed to show benefit in reducing SFA intake on type 2 diabetes incidence [83, 84]. Rather, there is evidence to sup- port an inverse relationship between the intake of dairy prod- ucts that are typically high in SFA and type 2 diabetes, which furthers brings current dietary recommendations to decrease SFA into question [85–87]. is associated with a shift in the population of the gut flora toward one that is rich in Firmicutes and deficient in Bacteroidetes. This altered Firmicutes/Bacteroidetes ratio is associated with obesity, inflammation, and chronic diseases, including CVD. Landmark studies by Hazen and colleagues, identified a bacterially derived metabolite, trimethylamine (TMA) that is converted by the human liver into the athero- genic molecule, trimethylamine N-oxide (TMAO). This ath- erogenic metabolite is generated from phosphatidylcholine (lecithin), choline, and carnitine in the diet [90–93]. While these molecules are components of red meat and shellfish, they are also components of highly processed food, especially lecithin. One of the common uses for soy lecithin is as an emulsifier inprocessed foods to improve texture and miscibil- ity of the ingredients. While it is important to isolate nutrients for experimental design, it can be difficult when translating findings for human diet development to know what compo- nent is contributing the most to disease phenotype. The development of atherosclerosis is impacted by multi- ple factors, including genetics, lifestyle, and diet-microbiota interactions. It is the modifiable nature of diet that lends itself to the possibility of intervention. By minimizing processed foods and choosingwell-sourced protein aspartof a complex, plant-based diet with minimally processed fats, we can try to minimize the risk of CVD promoting factors. Fiber, specifi- cally SCFA, can support the maintenance of a healthy microbiome that can minimize inflammation and protect against microbiota-mediated disease [9, 94–96]. Data from both human and animal studies implicate processed food ad- ditives (i.e., emulsifiers) in promoting obesity, metabolic syn- drome, and inflammation via gut-mediated interactions [97–99]. When considering the role of saturated fat, it may be prudent to think about the foods that saturated fat are tra- ditionally found in meats, shellfish, and processed food and consider that perhaps SFA may not be the ultimate causal factor for CVD but rather, an innocent bystander. As our un- derstanding of the relationship between diet and the microbiome evolves, we are sure to uncover more about the complex and nuanced role of our diet and the development or prevention of disease. Understanding How to Incorporate Saturated Fat: What Is a Balanced Diet? Diet and the Microbiome Traditionally, nutritional advice and the research community have focused on single macro- or micro-nutrients; while this strategy worked to prevent nutritional deficiencies, it does not work for health promotion and prevention of non- communicable diseases. We now recognize that the interde- pendent relationship between different dietary components is more important to overall health than a single component [100]. In recent years, it has become increasingly apparent that the gut microbiota-host relationship is incredibly important for interfacing with our diet and modulating human metabolism. The microbiome—composed of the bacteria that live in our gut,theirDNA,andthemetabolitestheyproduce—affectsour health and metabolism on a daily basis [88, 89]. The standard Western diet that is high in fat, high in sugar, and low in fiber,

  10. Curr Nutr Rep that were closer in fatty acid composition to grass-fed cattle with higher levels of omega-3 fatty acids than the over- consumed and cheaply produced grain-fed beef that we now findonour supermarket shelves.Historically, mostofthe beef produced in the USA until the 1940s was from cattle finished on grass with use of the feedlot starting in the 1950s. Just as our health is driven by our diet, so is the health, nutrient content, and fat composition of the animals we eat. The con- ventional beef available today is not the same beef that our ancestors ate. To make these findings actionable, perhaps the best dietary advice has been given by author Michael Pollan, “Eat food. Not too much. Mostly plants.” Within that simple statement, he encompasses the need to eliminate “edible food-like sub- stances” and focus on real, whole food, like fresh vegetables, pasturedmeatand dairy, and wholegrainsastheyare found in nature.Byeliminatingthehighlyprocessedflours,sugars,and factory-farmed meat, we will likely improve our health by drastically cutting out chemical additives, antibiotics, high- glycemic carbohydrates, and industrial forms of omega-6 lad- en vegetable oil. After all, the list of “saturated fat” that is often used to quantify intake of SFA includes pastries, pizza, and confectionaries. These foods not only have SFA, but they have excessive amounts of sugar and salt. Decreasing the processed food will not only decrease the potential for poor quality oxidized fat, but it will also decrease our intake of the insulin-spiking carbohydrates that have supplanted the natural sources of saturated fat that are beneficial to our overall health. The Framingham Heart Study, which has been highly in- fluential in this arena, demonstrated a link between partici- pants with high TG (>1.7 mmol/L) and low HDL (aka “good cholesterol” <1.03) levels and increased rates of CAD as op- posed to those with low TG and higher HDL cholesterol [101]. While this correlation remains true, the particular ben- efitsofalow-fatdietinalteringthisrelationshiphavenotbeen evaluated long-term and have had inconsistent results. In a cross-over dietary intervention study that compared different fat to carbohydrate macronutrient ratios using iso-caloric diets (60% carb, 25% fat, 15% protein vs. 40% carb, 45% fat, and 15% protein), they found higher plasma TG and lower HDL levelswithnoLDLeffectwhen participantswereassignedthe highercarbohydratedietdespite lowerfat intake[102].Rather than focus on total cholesterol, or even LDL cholesterol, it is more important to evaluate the contribution of the more ath- erogenic lipoprotein particles. The discrimination among these different particle sizes and densities has not been ade- quately used as a measure of CAD risk in the majority of the epidemiological studies upon which we have based our dog- ma. None of these lipoprotein molecules exist in a vacuum; rather, itisthecomplex interplaybetweenHDL,LDL,VLDL, and triglycerides that impact CAD risk [25]. When reducing one macronutrient component from the di- et, like SFA, we replace it with another. This replacement can have different impacts on host physiological response. Both the AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk [103] and the National Lipid Association Expert Panel [104] have stated that replacing SFAwith unsaturated fat (PUFA followed by MUFA) or pro- tein has more favorable impacts on lipid profiles than replace- mentwithcarbohydrates[35].Thisalsoappearstobesupport- ed in the multiple meta-analyses and Cochrane reviews on the topic; modifying fat intake by switching from SFA to an al- ternative source of fat appears to be more beneficial than in- creasing carbohydrate intake [45, 70]. However, there is evi- dence (see earlier sections) that large amounts of omega 6 PUFA may be contributing to the development of CVD. These factors may account for the increased incidence of obe- sity and CVD after the introduction of dietary guidelines geared at increasing carbohydrate intake in favor of lowering total fat. Sadly,itisnotasstraightforwardasremovingorembracing allsaturatedfat.Asdemonstrated,saturatedfatcomesinmany different types with unique physiological roles and conse- quences. Further, our food system today is not the same as it was pre-industrial and -agricultural revolutions. This pre- agricultural hunter-gatherer population subsisted on 45–65% of intake from animal-based food [105]. Despite their high intake of saturated animal fat, this population did not have the risk or incidence of CHD that we see now in Western populations [106]. This makes sense when considering that our paleolithic ancestors consumed wild game and ruminants Conclusions The relationship between what we eat and our health is com- plex. To focus on simplistic associations between single die- tary components as opposed to our diet composition and food sourcingonthewholeisequivalenttonotbeingabletoseethe forest for the trees. We need to examine foods and dietary patterns as a whole to fully understand their implications for human health and prevention of disease. The existing evi- dence does not support the notion that dietary SFA causes heart disease. There is no demonstrable benefit for reducing SFA to <10% dietary fat. We have eschewed the naturally formed saturated fats found in plant and animal products and replacedthemwithhighlyprocessed and chemicallyextracted linoleic acid-rich vegetable oils (i.e., corn oil, soybean oil, etc.) that are now found in our food supply at alarming rates. Inreturn, wehaverisingrates ofobesity, metabolic syndrome, and cardiovascular disease. Based on the existing evidence, saturated fats are a vital component of a healthy diet when they are naturally occurring and eaten in the context of a minimally processed diet.

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