Showing posts with label PUFA. Show all posts

Saturday, June 8, 2013

Dietary Fats and Health - Lawrence

Dietary Fats and Health: Dietary Recommendations in the Context of Scientific Evidence¹

Glen D. Lawrence^* Department of Chemistry and Biochemistry, Long Island University, Brooklyn, NY

*To whom correspondence should be addressed. E-mail: lawrence@liu.edu.

Abstract

Although early studies showed that saturated fat diets with very low levels of PUFAs increase serum cholesterol, whereas other studies showed high serum cholesterol increased the risk of coronary artery disease (CAD), the evidence of dietary saturated fats increasing CAD or causing premature death was weak. Over the years, data revealed that dietary saturated fatty acids (SFAs) are not associated with CAD and other adverse health effects or at worst are weakly associated in some analyses when other contributing factors may be overlooked. Several recent analyses indicate that SFAs, particularly in dairy products and coconut oil, can improve health. The evidence of ω6 polyunsaturated fatty acids (PUFAs) promoting inflammation and augmenting many diseases continues to grow, whereas ω3 PUFAs seem to counter these adverse effects. The replacement of saturated fats in the diet with carbohydrates, especially sugars, has resulted in increased obesity and its associated health complications. Well-established mechanisms have been proposed for the adverse health effects of some alternative or replacement nutrients, such as simple carbohydrates and PUFAs. The focus on dietary manipulation of serum cholesterol may be moot in view of numerous other factors that increase the risk of heart disease. The adverse health effects that have been associated with saturated fats in the past are most likely due to factors other than SFAs, which are discussed here. This review calls for a rational reevaluation of existing dietary recommendations that focus on minimizing dietary SFAs, for which mechanisms for adverse health effects are lacking.

Introduction

Since the Framingham Heart Study reported that high serum cholesterol was a major risk factor for coronary heart disease (1), there has been an aggressive campaign in the medical community to decrease serum cholesterol. It has been a widely accepted belief that dietary saturated fats and dietary cholesterol cause an increase in serum total cholesterol, as well as LDL-cholesterol (LDL-C)² and thereby increase the risk of heart disease if consumed (2). Over the years, it became clear that high levels of LDL circulating in the blood are susceptible to lipid peroxidation, which results in the oxidized LDL being scavenged by macrophages lining certain arteries, particularly around the heart, leading to atherosclerosis (3). Although this mechanism provides a role for high serum LDL-C causing atherosclerosis, evidence of the involvement of saturated fats is lacking, even though it is well established that a diet high in saturated fat increases serum cholesterol and a diet high in polyunsaturated oil decreases serum cholesterol (4, 5). In fact, PUFAs are the components that are oxidized and generate antigenic substances that are recognized by immune cells for clearance of oxidized LDL in atherogenesis (6–8).

Numerous reports and reviews in recent years have begun to call the perceived pernicious effects of dietary saturated fatty acids (SFAs) into question. The purpose of this review is to summarize the scientific understanding as it relates to dietary fats in health and disease, particularly with regard to the innocuous nature of SFAs and the physiological effects that have implicated PUFAs in numerous disorders and diseases. The role of dietary fats in cardiovascular disease (CVD) and many other diseases is complex, yet there is a powerful inertia that has allowed the saturated fat doctrine to endure.

Dietary fatty acids and serum cholesterol

Dietary fat studies in the mid-20th century stressed the relationship of dietary SFAs and PUFAs to serum cholesterol levels with an aim toward decreasing the likelihood of the development of coronary artery disease (CAD) and premature death (4, 5). Once lipoprotein fractions were separated in the blood, it became evident that LDL and VLDL were the carriers of cholesterol that were most closely associated with risk of heart disease (9). Later it was found that the ratio of total serum cholesterol to HDL-C was a better indicator of heart disease risk (10). By the 1990s, the mechanisms by which dietary fats and specific types of fatty acids were regulating serum cholesterol and lipoproteins were beginning to be revealed.

A family of proteins known as sterol regulatory element binding proteins (SREBPs) were discovered in the early 1990s. These proteins move to the nucleus in cholesterol-depleted cells to alter transcription of several genes involved in lipid metabolism (11). When intracellular cholesterol levels are low, SREBP-1 promotes expression of genes for synthesis of cholesterol and LDL receptors that remove cholesterol from the circulation. When intracellular cholesterol levels are high, SREBP-1 is not activated by protease cleavage, and the genes for cholesterol production and LDL receptors are downregulated. SREBP-1 also activates promoters for genes involved in fatty acid synthesis and lipid storage (12). PUFAs, particularly docosahexaenoic acid and others to a lesser extent, regulate expression of the SREBP genes (13, 14). Consequently, when PUFAs are present, there is less expression of SREBPs and enzymes for cholesterol synthesis, and the serum cholesterol pool decreases.

There appears to be a number of proteins that bind PUFAs and are involved in regulating gene expression, including a family of G protein–coupled receptors (15), as well as peroxisome proliferator–activated receptors-α and -γ, retinoid X receptors, and various other nuclear receptors (16). The liver uses a variety of these receptors or sensors for PUFAs to regulate storage and utilization versus oxidation of PUFAs (17). In this way, PUFAs can stimulate fatty acid oxidation in the liver to minimize their potential for free radical oxidation in the body when their levels are high in the diet. One must keep in mind that this complex array for regulation of expression of a wide range of genes is also subject to an even more complex array of responses to dietary PUFAs and other dietary factors.

Single nucleotide polymorphisms in genes for many of the above factors, as well as in genes for several apolipoproteins, TNFs, glutathione peroxidases, and other proteins result in a wide range of individual responses to dietary constituents. The consequences of such genetic variation can be either little change or very large changes in serum lipids and lipoproteins in response to diet, depending on an individual’s genetic makeup (18). However, one should not lose sight of the fact that levels of many other proteins are being altered in the process, which can give rise to a wide array of physiological responses that influence susceptibility to many unhealthy conditions, such as CVD and cancer.

Short-chain SFAs, such as those in dairy fat and coconut oil, can also influence gene expression via interactions with various G protein–coupled receptors that are linked to several hormonal responses, including insulin and leptin, that regulate overall energy metabolism in the body (19). It is clear that there are numerous sensors that respond to dietary PUFAs and short- or medium-chain SFAs (20).

Genetic factors

Brown and Goldstein (21) received the Nobel Prize in Physiology or Medicine in 1985 for their work on genetic defects in LDL receptors of people with familial hypercholesterolemia (FH). They identified several mutations that produce nonfunctional LDL receptors, resulting in death from atherosclerosis and heart disease at an early age. Individuals with FH have serum LDL-C in excess of 300 mg/dL (or 8 mmol/L), although LDL-C may be as high as 650 mg/dL (17 mmol/L) in homozygous individuals. Goldstein and Brown (22) also identified several genes that code for other proteins involved in cholesterol transport and metabolism, such as apolipoprotein B-100 (apo B), which is a component of LDL that binds to LDL receptors. There are other proteins involved in LDL synthesis, transport, and clearance that can result in a genetic predisposition to increased serum LDL cholesterol and FH (23–25).

In the early 1990s, it was discovered that men with CVD tended to have smaller HDL particles than healthy controls (26). It was later found that LDL particle size was also significantly smaller in men with CAD than in case-matched controls (27), although another study showed the ratio of total serum cholesterol to HDL-C was a better predictor of CAD risk than LDL particle size (28). A prospective, population-based cohort study also found an increased risk of CAD in middle-aged men with smaller, dense LDL particles than in men with larger LDL particles, although the relationship did not show a linear dependence on particle size (29). It later became evident that LDL particle size was influenced by several factors and was not necessarily a useful predictor of heart disease risk; the nature of LDL is influenced by both dietary and genetic factors (30).

Lipoprotein (a) [Lp(a)] is a complex lipoprotein that has several properties in common with LDL. Like LDL and VLDL, Lp(a) contains apo B, but also contains highly variable forms of apolipoprotein(a) that strongly influence its atherogenicity and propensity to promote heart disease (31). The wide array of apolipoprotein(a) isoforms present in the human population may have caused some confusion regarding the role of Lp(a) in atherogenesis and CVD. The association of apo B with oxidized phospholipids was found to be dependent on Lp(a) (32). The presence of oxidized phospholipids and Lp(a) tend to be proinflammatory and promote atherogenesis.

Small, dense LDL particles rarely occur as an isolated condition, but are often associated with a specific phenotype that is characterized by hypertriglyceridemia, low HDL-C, abdominal obesity, insulin resistance, and other metabolic irregularities that lead to endothelial dysfunction and susceptibility to thrombosis (33). Small, dense LDL is also more susceptible to lipid peroxidation due to changes in the lipid composition, making it more atherogenic (34). LDL particles from the atherogenic phenotype contain less cholesterol and phospholipid, but more triglyceride. This phenotype is generally referred to as phenotype B and is characterized by elevated levels of apo B, which is found in LDL and VLDL (35).

There have been a host of proteins linked to lipoprotein metabolism and transport and a wide range of genetic variations identified that result in alterations of those proteins. Many are associated with HDL and larger HDL particle size, which is consistently associated with a decreased risk of CAD (36). HDL is important in reverse-cholesterol transport, bringing cholesterol from arterial deposits to the liver for processing, where it is converted to useful metabolites and eventually cleared from the body via bile secretions. A family of lipoprotein lipases, including hepatic lipase and endothelial lipase, are intimately involved in HDL metabolism. Endothelial lipase is upregulated during inflammation, a condition that increases LDL oxidation and atherogenesis (37). Genetic variation in apolipoprotein A-I, a major protein component of HDL, can result in larger but less stable HDL particles and decreased levels of circulating HDL (38). Cholesteryl ester transfer protein is generally considered to be protective, although this protein may transfer lipids from HDL to other lipoproteins that result in a less desirable serum lipid profile (39). HDL is emerging as a fascinating lipoprotein with a complex array of functions that involve both protein and lipid components. HDL has been found to influence immune function, vascular inflammation, glucose metabolism, and platelet function as well as other physiological phenomena unrelated to CVD (40).

Paraoxonase 1 (PON1) is another protein associated with HDL that exhibits esterase and lactonase enzyme activity, including metabolism of toxic organophosphorus pesticides and oxidized lipids in oxidized LDL particles. The levels of PON1 activity varies tremendously among humans, which depends to a large degree on genetic variation. However, environmental factors, such as dietary antioxidant consumption, alcohol consumption, and certain drugs can also influence PON1 activity (41). Dietary olive oil can increase levels of serum PON1 in some individuals, which is genotype dependent (42), whereas MUFAs and PUFAs can inhibit PON1 enzymatic activity (43). SFAs (palmitic and myristic) had virtually no effect on PON1 enzymatic activity. A recent study found that HDL isolated from patients with CAD lacks endothelial anti-inflammatory properties, has lower PON1 enzyme activity, and does not promote endothelial nitric oxide production (44), all of which are most likely tied to genetic rather than dietary factors.

Fatty acids involved in atherogenesis and CVD

Linoleic acid makes LDL more susceptible to lipid peroxidation and subsequent deposition of the oxidized LDL in macrophages lining the arteries (45). Several lipid peroxidation products have been shown to trigger transformation of circulating monocytes to macrophages that line the arteries and ultimately become foam cells (46, 47). Lipid peroxidation products also signal cells in the arterial intima to encapsulate foam cells by surrounding them with extracellular matrix proteins and eventually calcify the matrix (48). It would stand to reason that a greater abundance of PUFAs, relative to SFAs and MUFAs, during conditions of oxidative stress would provoke atherogenesis. The fibrous cap that is formed over fatty deposits makes them inaccessible to apolipoproteins such as apolipoprotein A-I or E, which are components of HDL, the lipoprotein that removes cholesterol from these deposits (49). The protein cap is characteristic of advanced atherosclerotic plaque and erosion of this protective cap by extracellular metalloproteases can release collagen and collagen-like fragments that trigger blood platelets to initiate a blood clot, which results in myocardial infarction or stroke (3).

Because saturated fats are not susceptible to lipid peroxidation, they have not been found to be involved in these mechanisms. This begs the question of how dietary polyunsaturated oils seem to lower the risk of CAD, even though many studies have shown no such effect. One important consideration is that foods that are considered sources of predominantly saturated fats, such as meats, are often cooked at high temperatures, which can induce lipid peroxidation in the minor amounts of PUFAs present in those animal products (50–52). Oxidative stress and lipid peroxidation products are known to promote heart disease, cancer, and several other chronic diseases (53, 54). High-temperature cooking can also oxidize carbohydrates, producing a range of toxic oxidation products that promote oxidative stress, type 2 diabetes, and CVD (55). The preparation and cooking methods used for foods that are traditionally classified as saturated fat foods may be producing substances from PUFAs and carbohydrates in those foods that are promoting disease.

Human food preferences tend to favor foods with both fats and sugar (56), which complicates any attempts to correlate saturated fats with disease. Sugars readily undergo oxidation, with fructose generally getting oxidized many times faster than glucose, whereas sucrose is relatively resistant to oxidation (57). The oxidation products of these monosaccharides include glyoxal, methylglyoxal, and formaldehyde. Methylglyoxal has been shown to promote endothelial dysfunction as well as hypercholesterolemia in rats (58). Methylglyoxal is also associated with increased atherosclerosis and hypertension in humans (59). Formaldehyde and methylglyoxal have been implicated in endothelial injury, oxidative stress, and angiopathy (60).

Many clinical studies show that there are fewer coronary events when polyunsaturated oils replace saturated fats in the diet (61). However, a recent meta-analysis found that interventions using mixed ω3 and ω6 PUFAs resulted in a significant (22%) decrease in CAD events compared with control diets with fewer PUFAs. However, interventions that used ω6 polyunsaturated oils with no ω3 PUFAs showed ∼16% more cardiovascular events compared with the control diets, although the increased number was not statistically significant (62). It would seem that even moderate amounts of ω3 PUFAs in the diet result in attenuation of inflammatory responses that are reflected in the significant reduction in coronary events observed with increasing dietary PUFAs. Of the common vegetable oils, soy oil contains ∼7% ω3 PUFAs and canola oil as much as 10% ω3 PUFAs, whereas corn, safflower, and sunflower oils generally contain <1 a="" class="xref-bibr" href="http://advances.nutrition.org/content/4/3/294.long#ref-63" id="xref-ref-63-1" pufas="">63

). Another systematic review found insufficient evidence to support an association (positive or negative) between CAD and several dietary factors, including SFAs or PUFAs, α-linolenic acid, total fat, meat, eggs, and milk (64).

Lipid peroxidation and inflammation

Lipid peroxidation is invoked as a mechanism for numerous adverse health effects, such as aging, cancer, atherosclerosis, and tissue necrosis. The greater in vivo susceptibility of ω6 PUFAs relative to the ω3 PUFAs, has placed the spotlight on these fatty acids as contributing to or exacerbating many ailments (68). The metabolism of arachidonic acid to bioactive eicosanoids is responsible for many of the biological processes that lead to inflammation. Indeed, steroidal and nonsteroidal anti-inflammatory drugs suppress inflammation by blocking the release of arachidonic acid from membranes or its subsequent metabolism to eicosanoids.

Studies of inflammation in rats have found that dietary manipulation of relative amounts of ω6 PUFA precursors can have profound effects on the degree of inflammation. Predominantly SFAs in the diet result in far less inflammation than diets with either ω3 (69) or ω6 PUFAs (70). Several studies have shown that dietary supplementation with ω3 PUFAs can reduce inflammation and make patients less dependent on drug therapy to manage the pain and stiffness of arthritis (71–73). Patients should be advised to minimize their intake of ω6 oils when attempting ω3 supplementation as a therapeutic approach to reduce the inflammation of arthritis and other inflammatory syndromes (74, 75). Small amounts of ω3 supplements in a sea of dietary ω6 oils would have relatively little chance of changing the course of an inflammatory response. Because dietary saturated fats do not promote inflammation, it may be wiser to minimize ω6 PUFAs and consume more SFAs to reduce various types of inflammation; most sources of MUFAs contain significant amounts of PUFAs as well. There have been few scientific studies along these lines because of the misguided concern that saturated fats, even those from vegetable sources such as palm and coconut oil, would be detrimental to one’s health.

The efficacy of ω3 supplements for inflammatory syndromes other than rheumatoid arthritis are less persuasive, although study designs are questioned regarding whether patients are advised to reduce their ω6 fatty acid intake (76). Fish oil supplements improved pulmonary function in some asthmatics (responders) but not in others (nonresponders). A relatively high ratio (10:1) of dietary ω6 to ω3 PUFAs resulted in diminished respiratory function in methacholine-provoked asthmatics, whereas a lower ratio (2:1) produced significant improvement in >40% of the study participants (77). A study in Japan showed beneficial effects of ω3 supplements in asthmatic children in a controlled hospital ward environment (78). A comparison of dietary saturated fats with polyunsaturated oils was not found in the literature for asthma studies. Such an approach would be logical for this life-threatening condition, in view of the benign nature of saturated fats and the fact that carbohydrates, especially sugars, may actually be augmenting the incidence of asthma (79).

Are low-fat, low-saturated fat diets healthier?

Studies with laboratory animals have shown that high-fat diets promote chemically induced cancers (80, 81). A study of chemically induced mammary tumors in rats found that ω6 PUFAs promoted tumor proliferation, whereas saturated fats or ω3 PUFAs did not promote tumors as much or even suppressed tumors, depending on what one uses as a reference (82, 83). Although 1 review and meta-analysis found that linoleic acid, the predominant ω6 fatty acid in vegetable oils, is not a risk factor for breast, colorectal, and prostate cancers in humans (84), there is evidence to the contrary that high intake of ω6 relative to ω3 PUFAs increases cancer risks (85–87). There are multiple processes by which ω6 fatty acids can promote carcinogenesis; production of bioactive eicosanoids from arachidonic acid is 1 mechanism (88, 89). Nonsteroidal anti-inflammatory drugs as well as cyclooxygenase-2 inhibitors can suppress tumors by inhibiting production of prostaglandins, particularly those of the ω6 variety (90). Lipid peroxides are also known to promote chemically induced tumors (91), and PUFAs are highly susceptible to lipid peroxidation.

Investigators often seem to have a particular bias against saturated fats. One report showed that red meat alone was not significantly associated with colorectal cancer, although there was some increase in colorectal cancers with higher red meat intake [HR = 1.17 for highest vs. lowest intakes (95% CI = 0.92–1.49, P_-trend = 0.08)]. Processed meats were significantly associated [HR = 1.42 (95% CI = 1.09–1.86, P_-trend = 0.02)]. The authors then combined the data for red meat and processed meat to give a significant association and concluded that red and processed meat are positively associated with colorectal cancer (92). When specific types of meat were analyzed, significant risk was associated with pork [HR = 1.18 (95% CI = 0.95–1.48, P_-trend = 0.02)] and lamb [HR = 1.22 (95% CI = 0.96–1.55, P_-trend = 0.03)], but not with beef/or veal [HR = 1.03 (95% CI = 0.86–1.24, P_-trend = 0.76)]. It is interesting to note that in 1 study, beef had a much lower ratio of PUFAs to SFAs than pork, but nearly the same ratio of PUFAs to SFAs as sheep (93). The ratio of MUFAs to SFAs in beef also varies, as it does in most meats, with the ratio ranging from ∼0.8 to 1.8, depending on breed and feeding practices (94).

Nitrite used in the preservation of many processed meats is known to form a carcinogen with secondary amines under acidic conditions that would prevail in the stomach (95). Others have found no association of red meat and only a very weak association of processed meat with breast cancer (96) and prostate cancer (97). Most studies find no differences in cancer risk with different types of fat, but do find associations with high levels of fat in the diet (81).

A recent meta-analysis (98) reviewed 20 studies with >1 million subjects and found that red meat was not associated with CAD events [RR = 1.00 (95% CI = 0.81–1.23, P_-trend = 0.36)]. In contrast, processed meats were associated with increased incidence of CAD [RR = 1.42 (95% CI = 1.07–1.89, P_-trend = 0.04)]. This indicates that saturated fat per se is not increasing CAD events, but other factors are, such as preservatives used in processed meats or other dietary substances that are being consumed in conjunction with processed meats. It is important to keep in mind that meats generally contain as much MUFA as SFA. Others are beginning to challenge the saturated fat hypothesis with closer analyses of past studies (99–103).

Campaigns were waged against tropical oils (palm and coconut oils) in the early 1980s because of their high levels of SFAs, even though palm oil contains about as much MUFAs acids as SFAs and has an ample amount of PUFAs to keep serum cholesterol low. In fact, 2 studies showed that the higher ratio of SFAs to MUFAs in palm oil (1.1:1) compared with olive oil (0.22:1) had no effect on serum lipids in healthy volunteers (104, 105). Palm oil and olive oil have similar amounts (∼10%) of PUFAs. SFAs in coconut oil increase serum HDL-C more than LDL-C to give a more favorable lipid profile relative to dietary carbohydrates (10). Claims that tropical oils with a high SFA content increase the risk of CAD lack clear scientific evidence to that effect. Indeed, countries with high intake of tropical oils have some of the lowest rates of heart disease in the world (106).

Many of the shorter chain fatty acids found in milk fat and coconut oil have beneficial health effects. The shorter chain SFA in milk (C4–C12) are not only metabolized rapidly for energy in infants, but have been found to have important antiviral, antimicrobial, antitumor, and immune response functions (107). Lauric acid, which is present in milk and the most abundant fatty acid in coconut oil, is effective in preventing tooth decay and plaque buildup (108). Diets rich in coconut oils have also been shown to lower other risk factors for CAD, such as tissue plasminogen activator antigen and Lp(a) (109). The medium-chain SFAs in coconut oil and butterfat (milk) increase total serum cholesterol, but their positive effects on HDL-C are protective in many ways. There is also evidence that proteins, fats, and calcium in milk are beneficial in lowering blood pressure, inflammation, and the risk of type 2 diabetes (110, 111). Indeed, these constituents of milk have clear beneficial effects against metabolic syndrome, which is a major factor in promoting heart disease, as well as premature death from a variety of causes (112).

There has been a spate of recent publications in the biomedical literature that question the negative perception that dairy fats are bad for health. One meta-analysis showed that participants in prospective studies with the highest consumption of dairy products had a lower RR for all-cause mortality as well as for CAD, stroke, and diabetes compared with the lowest intake of dairy products (113). Many of the studies included in the analysis started before low-fat milk was available on the market. Another review arrived at the same conclusion that consumption of dairy products is not associated with higher risk of CVD (100). Although prospective cohort studies often find a significant reduction in the incidence of CAD with a larger ratio of PUFAs to SFAs in the diet (114), there are often many other factors related to overall health that correlate with the unsaturated to SFA ratio, such as exercise, a healthier lifestyle, and more fiber and less sugar in the diet.

Less fat generally means more carbohydrate

It should not be surprising that substitution of carbohydrates (starches) for saturated fats in the diet has relatively little effect on serum lipids. Excess carbohydrates are converted to fats for efficient energy storage, and the human body synthesizes primarily SFAs from excess carbohydrates, although MUFAs are also formed. Consequently, from a physiological viewpoint, there is no reason to believe that replacing fat in the diet with carbohydrate at a constant caloric intake will improve the serum lipid profile significantly. Indeed, a low-fat, high-carbohydrate diet causes an increase in serum triglycerides and small, dense LDL particles (115), which are more strongly associated with CAD than serum total cholesterol or LDL-C. When dietary fat is replaced by carbohydrate without changing the fatty acid composition of the fat, there is no change in LDL-C or HDL-C, but there is an increase in serum triglycerides (116). However, if there is a higher percentage of PUFAs and lower SFAs in a low-fat diet, serum total cholesterol and LDL-C will decrease (117).

Young children who consumed more fruit juice than their peers were shorter in stature and had greater BMI than their peers who drank less fruit juice (118). A trend of increased fruit juice consumption by infants and children in recent years has coincided with a decrease in milk consumption (119). The rates of childhood obesity have skyrocketed since the introduction of low-fat milk, although high fructose corn syrup (HFCS) became omnipresent in foods at the same time and is more strongly associated with obesity than dietary fat (120, 121). As stated previously, the short-chain SFAs in milk provide valuable antibacterial and antiviral activities, which would result in healthier children. The short-chain SFAs found in milk act as signaling agents in the immune system (122). Infections in children also correlated with higher levels of atherogenic oxidized LDL, as well as lower levels of HDL (123). It is possible that oxidized LDL and low HDL impart increased susceptibility to infection, although the combination of infections and an adverse serum lipid profile may both result from an undesirable diet, i.e., more sugar and fewer healthy fats.

Food processors generally add large amounts of sugar to fat-free or low-fat foods to make them more palatable to consumers. Fructose is 1 dietary constituent that is consistently found to have adverse health consequences, and the larger the proportion of fructose is in the diet, the more formidable the effect. The adverse effects of fructose that have been documented include increased serum triglycerides, particularly in men (124, 125); increased serum uric acid, which is associated with gout and hypertension (126); increased lipid peroxidation (57) and increased oxidation of LDL (127); increased oxidative stress in animal models (128); greater risk of the development of metabolic syndrome, including obesity, insulin resistance, hypertension, and CVD risk (129, 130); increased nonalcoholic fatty liver disease (131); and increased systemic inflammation and associated renal disease (132).

There are clearly many established physiological mechanisms by which fructose increases CVD and several other diseases. Whether the source of dietary fructose is sucrose or HFCS would seem irrelevant, although sucrose is 50% fructose, whereas the most common dietary source of HFCS (soft drinks) is generally 55% fructose and ∼43% glucose. Solutions of fructose are also highly susceptible to autoxidation, producing a host of toxic products (57), whereas sucrose is highly resistant to oxidation. The toxic products from fructose oxidation include formaldehyde and α-dicarbonyls. Although saturated fats have been implicated in many of the adverse health effects attributed to fructose, there is no scientific evidence to support a role for saturated fats in the physiological mechanisms. On the other hand, plausible mechanisms are proposed for all of the unhealthy conditions promoted by high fructose intake mentioned earlier.

It turns out that a high level of fructose in the diet increases plasma triglycerides, which leads to not only increased levels of VLDL and small, dense LDL particles, but increased levels of oxidized LDL, insulin resistance, and other metabolic consequences linked to metabolic syndrome and dyslipidemia (133). The mechanisms by which fructose promotes inflammation and elevated levels of uric acid and several cytokines have been reviewed (132).

Conclusions

Saturated fats are benign with regard to inflammatory effects, as are the MUFAs. The meager effect that saturated fats have on serum cholesterol levels when modest but adequate amounts of polyunsaturated oils are included in the diet, and the lack of any clear evidence that saturated fats are promoting any of the conditions that can be attributed to PUFA makes one wonder how saturated fats got such a bad reputation in the health literature. The influence of dietary fats on serum cholesterol has been overstated, and a physiological mechanism for saturated fats causing heart disease is still missing.

Various aldehydes produced in the oxidation of PUFAs, as well as sugars, are known to initiate or augment several diseases, such as cancer, inflammation, asthma, type 2 diabetes, atherosclerosis, and endothelial dysfunction. Saturated fats per se may not be responsible for many of the adverse health effects with which they have been associated; instead, oxidation of PUFAs in those foods may be the cause of any associations that have been found. Consequently, the dietary recommendations to restrict saturated fats in the diet should be revised to reflect differences in handling before consumption, e.g., dairy fats are generally not heated to high temperatures. It is time to reevaluate the dietary recommendations that focus on lowering serum cholesterol and to use a more holistic approach to dietary policy.

Acknowledgments

The sole author had responsibility for all parts of the manuscript.

Footnotes

↵1 Author disclosure: G. D. Lawrence, no conflicts of interest.
↵2 Abbreviations used: apo B; apolipoprotein B-100; CAD, coronary artery disease; CVD, cardiovascular disease; FH, familial hypercholesterolemia; HDL-C, HDL cholesterol; HFCS, high fructose corn syrup; LDL-C, LDL cholesterol; Lp(a), lipoprotein(a); PON1, paraoxonase 1; SFA, saturated fatty acid; SREBP, sterol regulatory element binding protein.

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Monday, May 20, 2013

Dietary Fats and Health - Lawrence

Dietary Fats and Health

Glen D. Lawrence^* Department of Chemistry and Biochemistry, Long Island University, Brooklyn, NY

Abstract

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Read the complete article from Advances in Nutrition here.

Thursday, September 13, 2012

Association Between Omega-3 Fatty Acid Supplementation & Risk of Major Cardiovasular Disease - Harris

Comment On JAMA publication by Rizo et.al: Association Between Omega-3 Fatty Acid Supplementation & Risk of Major Cardiovasular Disease

Written by William Harris PhD

Response on the JAMA publication: Association Between Omega-3 Fatty Acid Supplementation and Risk of Cardiovascular Disease Events: On September 12, 2012 Rizos et al. published a meta-analysis titled: “Association Between Omega-3 Fatty Acid Supplementation and Risk of Major Cardiovascular Disease Events” on fish oil and concluded no benefit. Spokespeople from the AHA have been on TV saying that omega-3 supplements clearly don’t ‘work’. here are some of my thoughts…

Positve view of the study

They included all relevant studies; they did not exclude (like the previous meta-analysis (Kwak) did) the non-placebo controlled trials (GISSI-Prevenzione and JELIS)

First negative view about the study

They showed in Figure 3 that there was a significant benefit of omega-3 on cardiac death, and trends towards benefit in total mortality, sudden death and MI (plus trends towards increased stroke). But in the text, they said that there was NO significant effect on cardiac death – this is because they set the p-value for significance at 0.006, a much higher hurdle (than the usual 0.05) for concluding benefit. In my view, this is completely inappropriate and excessively conservative, especially for a very safe intervention. In other words, if you are testing a new drug that has potential benefits AND side/adverse effects, then you want to be very conservative in concluding “benefit” (i.e., you want to require a very small p-value) since – if you’re wrong and the drug really isn’t helpful (false positive) - your ‘endorsement’ of the drug will lead to increased use and thus the potential for increased adverse effects. However, for very low risk interventions (n-3 fatty acids), you don’t worry about adverse effects… you want people to use the treatment even if there is only a trend towards benefit. A favorable benefit-risk ratio. (I’d even suggest that in this setting, a p-value for ‘significant effect’ should be 0.1 instead of the traditional 0.05). In addition, nobody I know of ever adjusts for multiple testing (sets a lower p-value than 0.05 as the target for significance) in a meta-analysis. Therefore, I believe that the authors were far too conservative in this analysis, which led to their “no benefit” conclusion.

Second negative view about the sudy

They should have been much more nuanced in their conclusions. They said, “Our findings do not justify the use of omega-3 in structured [?] intervention in everyday clinical practice or guidelines supporting dietary omega-3 PUFA administration.” They should have said, “In patients of average age 63, with existing cardiovascular disease and under optimal medical care (which, by the way, is very UNcommon), the administration of about 1 g of EPA+DHA for 4 years will not affect major clinical outcomes.” Their study does NOT show that treating with a higher dose for a longer period of time, or treating patients earlier in the disease process or those who are not receiving “optimal medical therapy” will NOT be beneficial.

There may (or may not!) be a slight silver lining to all of this: Here is what Tom Barringer and I ended a chapter on n3 and CVD with in an upcoming book on “Omega-3 Deficiency”:
It should be stressed that future research will be significantly hampered if clinicians and patients are dogmatic in their belief that the value of n-3 fatty acids in CVD is already well-established. If such unfounded certainty is widespread, it will become very difficult to find patients (and investigators and IRBs) willing to participate in or approve the placebo-controlled clinical trials that are so desperately needed to properly evaluate the value of these nutrients in the treatment and prevention of CVD.”
Clearly with Rizos’ paper, we now won’t have any problem convincing the world that the question of omega-3s and CHD risk is still open.

In summary, they were too conservative in their analysis and they were not thoughtful in drawing their conclusions. It’s quite likely true that 1 g of EPA+DHA won’t affect outcomes over a few years in older people started later in life who are well-treated pharmacologically – but that’s a far cry from USA Today’s Headline “Fish oil pills with omega-3 don’t help against disease”
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William Harris PhD

Senior Scientist
William Harris holds a PhD in Nutritional Biochemistry from the University of Minnesota, and did 4 years of post-doctoral research at the Oregon Health Sciences University. He was Director of the Lipid Research Laboratories at the University of Kansas Medical Center (KUMC) and at the Mid America Heart Institute, both in Kansas City, MO, for 22 years, and was on the faculty at KUMC and at the University of Missouri-Kansas City School of Medicine. Between 2006 and 2011 was the Director of the Cardiovascular Health Research Center at Sanford Research/USD (Sioux Falls, SD).
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Friday, August 17, 2012

High fat diet during pregnancy leads to severe liver disease - Kresser

More silly shenanigans against saturated fat

Seriously. I cannot believe the stuff that gets published in medical journals these days. I don’t know which is the scarier possibility: that the researchers are really so poorly trained that they consistently violate the most basic principles of medical research (that you probably learned in your 8th grade science class), or that they are so dishonest that they intentionally and blatantly lie about their results.

A prime example of this is an article that came across my newsfeed a couple of days ago. The headline read “High fat diet during pregnancy leads to severe liver disease“. I’m always very, very suspicious when I see articles like this because of my previous experience evaluating such studies. All too often researchers make basic (and frankly, inexcusable) mistakes like lumping all fat types together (i.e. combining saturated fat with polyunsaturated fat, although the two fatty acids have completely different effects on human physiology).

I didn’t have time to review the study and write about it, so I emailed Chris Masterjohn, a researcher pursuing a PhD in Nutritional Sciences with a concentration in Biochemical and Molecular Nutrition at the University of Connecticut. Chris has a blog called The Daily Lipid where he writes about the benefits of saturated fat and the dangers of polyunsaturated fat. Turns out Chris had seen the article on ScienceDaily too and was planning to write a critique. Here’s what he wrote. I encourage you to check out his blog, and also his website, both of which have some great information about the health benefits of cholesterol and saturated fat.

According to a recent article on ScienceDaily, scientists have discovered that mothers who eat too much saturated fat during pregnancy will give their future child severe fatty liver disease once he or she becomes an adult.

The use of words in this article like “mother,” “child,” and “adulthood” suggests that the researchers performed some type of scientific research in humans. In fact, ScienceDaily goes so far as to claim that the researchers were studying the consumption of high-fat diets during “a woman’s pregnancy.”
Nowhere in the article do the authors inform the reader that the research was performed in mice. This is the first time I have ever read of a mouse referred to as a “woman.”

The most egregious distortion of the study, however, comes from one of the researchers himself:
Professor Christopher Byrne, with colleagues Dr Felino Cagampang and Dr Kim Bruce, of the University’s School of Medicine and researchers at King’s College London, conducted the study, funded by the BBSRC. Prof Byrne explained: “This research shows that too much saturated fat in a mother’s diet can affect the developing liver of a fetus, making it more susceptible to developing fatty liver disease later in life. An unhealthy saturated fat-enriched diet in the child and young adult compounds the problem further causing a severe form of the fatty liver disease later in adult life.”
Really, “saturated fat” causes liver disease? This stands in surprising contrast to other rodent studies showing that saturated fat prevents liver disease:

A 1995 paper in the journal Gastroenterology lauded “dietary saturated fatty acids” as “a novel treatment for alcoholic liver disease” after showing that substitution of saturated palm oil for polyunsaturated fish oil reduced alcohol-induced liver damage.
A more recent paper published in the Journal of Nutrition 2004 showed that saturated fat from MCT oil (medium-chain fats similar to those in coconut oil) and beef tallow reduced alcohol-induced liver damage when substituted for polyunsaturated corn oil. In fact, they replaced 20 percent, 45 percent, or two-thirds of the corn oil with saturated fat and found that the more saturated fat they used, the greater the protective effect.
An even more recent paper published in the journal Hepatology in 2005 found that rats fed corn oil readily developed liver damage when fed over a quarter of their calories as alcohol, but rats fed saturated cocoa butter were virtually immune to liver damage when consuming the same amount of alcohol.
A 2007 study published in the journal Nutrition and Metabolism found that although corn oil-based high-fat diets can induce non-alocholic fatty liver disease in rodents, long-term feeding of high-fat diets based on coconut oil or butter cannot.

So how is it that “saturated fat” wound up causing liver disease in the offspring of these mice?
If we look at “supplementary table 1,” we find that the “saturated fat” used in this study was mostly monounsaturated and polyunsaturated fat. In fact, 22 percent of the fat on the low-fat diet was saturated, while only 15 percent of the fat on the high-fat diet was saturated!

That means that less than seven percent of the calories from the “unhealthy saturated-fat-enriched diet” actually came from saturated fat.

The “unhealthy saturated fat-enriched diet” actually contained 44 percent of its fat as polyunsaturated fatty acids (PUFA) and almost twenty percent of its total calories as PUFA. This is in great excess of the PUFA consumption seen even in the Standard American Diet (SAD), loaded in processed PUFA-rich vegetable oils.

Apparently “saturated fat” consumed during a “woman’s pregnancy” leads to liver disease once the “child” reaches “adulthood” only when the “saturated fat” is the highly polyunsaturated kind one would find in corn oil and the “woman” is a light, fluffy critter no one would ever mistake for a human.

What can we learn from this study? Perhaps that we can never trust the news account of a research study. Unfortunately we cannot even trust the quotes in those news account taken from the researchers themselves.
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Read the full article here.

Friday, August 3, 2012

Liver saving saturated fats

August 2, 2012 by principleintopractice

As my last post started to explore, different types of dietary fats have different effects on the progression of alcoholic liver disease. This post will further explore the protective effects of saturated fats in the liver.

For many, the phrase “heart healthy whole grains” rolls off the tongue just as easily as “artery clogging saturated fats”. Yet where is the evidence for these claims? In the past few decades saturated fats have been demonized, without significant evidence to suggest that natural saturated fats cause disease (outside of a few well touted epidemiological studies). Indeed, most of the hypothesis-driven science behind the demonization of saturated fats is flawed by the conflation of saturated fats with artificial trans fats (a la partially hydrogenated soybean oil).

In the face of a lack of any significant scientific evidence that clearly shows that unadulterated-saturated fats play a significant role in heart disease (and without a reasonable mechanism suggesting why they might), I think the fear-mongering “artery clogging” accusations against saturated fats should be dropped. On the contrary, there is significant evidence that saturated fats are actually a health promoting dietary agent- all be it in another (though incredibly important) organ.

Again (from my last post), here is a quick primer on lipids (skip it if you’re already a pro). For the purpose of this post, there are two important ways to classify fatty acids. The first is length. Here I will discuss both medium chain fatty acids (MCFA), which are 6-12 carbons long, and long chain fatty acids (LCFA), which are greater than 12 carbons in length (usually 14-22; most have 18). Secondly, fatty acids can have varying amounts of saturation (how many hydrogens are bound to the carbons). A fatty acid that has the maximal number of hydrogens is a saturated fatty acid (SAFA), while one lacking two of this full complement, has a single double bond and is called monounsaturated (MUFA) while one lacking more (four, six, eight etc.) has more double bonds (two, three, four, etc.) and is called a polyunsaturated fatty acid (PUFA).

Next time you eat a good fatty (preferably grass-fed) steak, or relish something cooked in coconut or palm oil, I hope you will feel good about the benefits you are giving your liver, rather than some ill-placed guilt about what others say you are doing to your arteries. From now on, I hope you think of saturated fats as “liver saving (and also intestine preserving) lipids”. Here’s why:
In 1985, a multi-national study showed that increased SAFA consumption was inversely correlated with the development of liver cirrhosis, while PUFA consumption was positively correlated with cirrhosis [1]. You might think it is a bit rich that I blasted the epidemiological SAFA-heart disease connection and then embrace the SAFA-liver love connection, but the proof is in the pudding- or in this case the experiments that first recreated this phenomena in the lab, and then offered evidence for a mechanism (or in this case many mechanisms) for the benefits of SAFA.

The first significant piece of support for SAFA consumption came in 1989, when it was shown in a rat model that animals that were fed an alcohol-containing diet with 25% of the calories from tallow (beef fat, which by their analysis is 78.9% SAFA, 20% MUFA, and 1% PUFA) developed none of the features of alcoholic liver disease, while those fed an alcohol-containing diet with 25% of the calories from corn oil (which by their analysis is 19.6% SAFA, 23.6% MUFA, and 56.9% PUFA) developed severe fatty liver disease [2].

More recent studies have somewhat complicated the picture by feeding a saturated fatty-acid diet that combines beef tallow with MCT (medium chain triglycerides- the triglyceride version of MCFAs). This creates a diet that is more highly saturated than a diet reliant on pure-tallow, but it complicates the picture as MCFA are significantly different from LCFA in how they are absorbed and metabolized. MCFA also lead to different cellular responses (such as altered gene transcription and protein translation). Nonetheless, these diets are useful for those further exploring the role of dietary SAFA in health and disease.

These more recent studies continue to show the protective effects of SAFA, as well as offer evidence for the mechanisms by which SAFA are protective.

Before we explore the mechanisms, here is a bit more evidence that SAFAs are ‘liver saving’.
A 2004 paper by Ronis et al confirmed that increased SAFA content in the diet decreased the pathology of fatty liver disease in rats, including decreased steatosis (fat accumulation), decreased inflammation, and decreased necrosis. Increasing dietary SAFA also protected against increased serum ALT (alanine transaminase), an enzymatic marker of liver damage that is seen with alcohol consumption [3]. These findings were confirmed in a 2012 paper studying alcohol-fed mice. Furthermore, these researchers showed that SAFA consumption protected against an alcohol-induced increase in liver triglycerides [4]. Impressively, dietary SAFA (this time as MCT or palm-oil) can even reverse inflammatory and fibrotic changes in rat livers in the face of continued alcohol consumption [5].

But how does this all happen?
Before I can explain how SAFA protect against alcoholic liver disease, it is important to understand the pathogenesis of ALD. Alas, as I briefly discussed in my last post, there are a number of mechanisms by which disease occurs, and the relative importance of each mechanism varies based on factors such as the style of consumption (binge or chronic) and confounding dietary and environmental factors (and in animals models, the mechanism of dosing). SAFA is protective against a number of mechanisms of disease progression- I’ll expound on those that are currently known.
In my opinion, the most interesting (and perhaps most important) aspect of this story starts outside the liver, in the intestines.

In a perfect (healthy) world, the cells of the intestine are held together by a number of proteins that together make sure that what’s inside the intestines stays in the lumen of the intestine, with nutrients and minerals making their way into the blood by passing through the cells instead of around them. Unfortunately, this is not a perfect world, and many factors have been shown to cause a dysfunction of the proteins gluing the cells together, leading to the infamous “leaky gut”. (I feel it is only fair to admit that when I first heard about “leaky gut” my response was “hah- yeah right”. Needless to say, mountains of peer-reviewed evidence have made me believe this is a very real phenomenon).
Intestinal permeability can be assessed in a number of ways. One way is to administer a pair of molecular probes (there are a number of types, but usually a monosaccharide and a disaccharide), one which is normally absorbed across the intestinal lining and one that is not. In a healthy gut, you would only see the urinary excretion of the absorbable probe, while in a leaky gut you would see both [6]. Alternatively, you can look in the blood for compounds such as lipopolysaccharide (LPS-a product of the bacteria that live in the intestine) in the blood. (Personally, I would love to see some test for intestinal permeation become a diagnostic test available to clinicians.)

Increased levels of LPS have been found in patients with different stages of alcoholic disease, and are also seen in animal models of alcoholic liver disease. Increased levels of this compound have been associated with an increased inflammatory reaction that leads to disease progression. Experimental models that combine alcohol consumption and PUFA show a marked increase in plasma LPS, while diets high in SAFA do not.

But why? (Warning- things get increasingly “sciencey” at this point. For those less interested in the nitty-gritty, please skip forward to my conclusions)

Cells from the small intestine of mice maintained on a diet high in SAFA, in comparison to those maintained on a diet high in PUFA, have significantly higher levels of mRNA coding for a number of the proteins that are important for intestinal integrity such as Tight Junction Protein ZO-1, Intestine Claudin 1, and Intestine Occludin. Furthermore, alcohol consumption further decreases the mRNA levels of most of these genes in animals fed a high-PUFA containing diet, while alcohol has no effect on levels in SAFA-fed animals. Changes in mRNA level do not necessarily mean changes in protein levels, however the same study showed an increase in intestinal permeability in mice fed PUFA and ethanol in comparison to control when measured by an ex-vivo fluorescent assay. This shows that PUFA alone can disturb the expression of proteins that maintain gut integrity, and that alcohol further diminishes integrity. In combination with a SAFA diet, however, alcohol does not affect intestinal permeability [4].

Improved gut integrity is no doubt a key aspect of the protective effects of SAFA. Increased gut integrity leads to decreased inflammatory compounds in the blood, which in turn means there will be decreased inflammatory interactions in the liver. Indeed, in comparison to animals fed alcohol and PUFA, animals fed alcohol with a SAFA diet had significantly lower levels of the inflammatory cytokine TNF-a and the marker of macrophage infiltration MCP-1 [4]. Decreased inflammation, both systemically and in the liver, is undoubtedly a key element of the protective effects of dietary SAFA.
This post is already becoming dangerously long, so without going into too much detail, it is worth mentioning that there are other mechanisms by which SAFA appear to protect against alcoholic liver disease. Increased SAFA appear to increase liver membrane resistance to oxidative stress, and also reduces fatty acid synthesis while increasing fatty acid oxidation [3]. Also, a diet high in SAFA is associated with reduced lipid peroxidation, which in turn decreases a number of elements of inflammatory cascades [5]. Finally- and this is something I will expand on in a future post- MCFAs (which are also SAFA) have a number of unique protective elements.

I realize that this post has gotten rather lengthy and has brought up a number of complex mechanisms likely well beyond the level of interest of most of my readers…

If all else fails- please consider this:
The “evidence” that saturated fats are detrimental to cardiac health is largely based on epidemiological and experimental studies that combined saturated fats with truly-problematic artificial trans-fats. Despite the permeation of the phrase “artery clogging saturated fats”, I have yet to see the evidence nor be convinced of a proposed mechanism by which saturated fats could lead to decreased coronary health.

ON THE CONTRARY…
There is significant evidence, founded in epidemiological observations, confirmed in the lab, and explored in great detail that shows that saturated fats are protective for the liver. While I have focused here on the protective effects when SAFA are combined with alcohol, they offer protection to the liver under other circumstances, such as when combined with the particularly liver-toxic pain-killer Acetaminophen [7].

Next time you eat a steak, chow down on coconut oil, or perhaps most importantly turn up your nose at all things associated with “vegetable oils” (cottonseed? soybean? Those are “vegetables”?), know that your liver appreciates your efforts!

1. Nanji, A.A. and S.W. French, Dietary factors and alcoholic cirrhosis. Alcohol Clin Exp Res, 1986. 10(3): p. 271-3.
2. Nanji, A.A., C.L. Mendenhall, and S.W. French, Beef fat prevents alcoholic liver disease in the rat. Alcohol Clin Exp Res, 1989. 13(1): p. 15-9.
3. Ronis, M.J., S. Korourian, M. Zipperman, R. Hakkak, and T.M. Badger, Dietary saturated fat reduces alcoholic hepatotoxicity in rats by altering fatty acid metabolism and membrane composition. J Nutr, 2004. 134(4): p. 904-12.
4. Kirpich, I.A., W. Feng, Y. Wang, Y. Liu, D.F. Barker, S.S. Barve, and C.J. McClain, The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic toll-like receptor expression in a mouse model of alcoholic liver disease. Alcohol Clin Exp Res, 2012. 36(5): p. 835-46.
5. Nanji, A.A., K. Jokelainen, G.L. Tipoe, A. Rahemtulla, and A.J. Dannenberg, Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration. J Pharmacol Exp Ther, 2001. 299(2): p. 638-44.
6. DeMeo, M.T., E.A. Mutlu, A. Keshavarzian, and M.C. Tobin, Intestinal permeation and gastrointestinal disease. J Clin Gastroenterol, 2002. 34(4): p. 385-96.
7. Hwang, J., Y.H. Chang, J.H. Park, S.Y. Kim, H. Chung, E. Shim, and H.J. Hwang, Dietary saturated and monounsaturated fats protect against acute acetaminophen hepatotoxicity by altering fatty acid composition of liver microsomal membrane in rats. Lipids Health Dis, 2011. 10: p. 184.
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Read the complete article here.

Sunday, March 25, 2012

Good Fats, Bad Fats: Separating Fact from Fiction

Written by Chris Masterjohn March 24 2012

Few driving factors have had such a profound influence on the transition from traditional to modern industrial diets as the campaign against animal fats and tropical oils. We have responded to this campaign not only by depriving ourselves of the nutrient-dense animal foods so important to human health, but also by replacing these traditional fats with processed foods laden with refined vegetable oil, flour, and sugar.

Since its inception, this campaign has been based on a series of myths. These include the myths that saturated fat is the “bad fat” while polyunsaturated fat is the “good fat,” that arachidonic acid is the “bad fat,” and that so-called “solid fats” are empty calories with no nutritional value. We will consider each of these myths in the pages that follow.

MYTH 1: SATURATED FAT IS BAD, POLYUNSATURATED FAT IS GOOD

The myth that saturated fatty acids are “bad fat” while polyunsaturated fatty acids (PUFA) are “good fat” emerged in the 1950s as the dietheart hypothesis. This hypothesis stated that the saturated fat found in animal fats and tropical oils would contribute to heart disease by raising blood cholesterol levels while the PUFA found in vegetable oils would do just the opposite.

If the nutritional and medical establishments had taken the approach of Weston Price and endeavored to begin unraveling the causes of heart disease by studying the diets and lifestyles of populations that were immune to the disease, it is unlikely the diet-heart hypothesis would ever have emerged. The traditional diets of Pacific islanders free of heart disease, for example, vary widely in their proportions of fat and carbohydrate, but as can be seen in Figure 1, they are all rich in saturated fat and low in PUFA when compared to the standard American diet.^1,2,3 Each of these traditional diets is based primarily on starches, fruits, coconut and fish, so the PUFA comes mostly from fish rather than from vegetable oils.

The foundation of the establishment’s approach to the riddle of heart disease featured no such investigation of traditional diets, and the result of this negligence was the diet-heart hypothesis. Advocates of this hypothesis supported it in the early 1950s with two key pieces of evidence. The first was that blood cholesterol levels were statistically associated with heart disease risk.⁴ The second was that, in highly controlled laboratory experiments, replacing saturated fats like butter, lard or coconut oil with polyunsaturated oils like corn or safflower oil would lower blood cholesterol levels.^5,6 Playing a game of connect the dots, they argued that substituting vegetable oils for traditional animal fats and tropical oils would lower the risk of heart disease.

In 1957, the American Heart Association called the hypothesis “highly speculative,” and concluded that “the evidence at present does not convey any specific implications for drastic dietary changes, specifically in the quantity or type of fat in the diet of the general population, on the premise that such changes will definitely lessen the incidence of coronary or cerebral artery disease.”⁷ Four years later, the state of the evidence remained the same but three members of the committee were dropped and replaced by four new members, including Ancel Keys, a leading proponent of the hypothesis. The updated report recommended that men who are overweight, have high blood pressure or high cholesterol, lead “sedentary lives of relentless frustration,” or have a strong family history of heart disease should replace part of the saturated fat in their diets with PUFA.⁸

The hypothesis nevertheless remained controversial in the scientific community for decades. The tide turned in 1984 when the Coronary Primary Prevention Trial showed that cholestyramine could prevent heart attacks.⁹ Cholestyramine is a drug that binds bile acids in the intestine and causes their excretion in the feces. As a result, the liver takes cholesterol in from the blood in order to make more bile acids and the concentration of cholesterol in the blood falls. Time magazine hailed the trial as a vindication of the American Heart Association’s twenty-three-year-old stance against animal fats. Butter, eggs, and bacon were all conspicuously absent from the treatment protocol of this trial, but Time nevertheless ran a cover story entitled “Hold the Eggs and Butter,” which artfully featured a frowning face with eyes of sunnyside up eggs and a downturned mouth of a slice of fried bacon. The article declared, “cholesterol is proved deadly, and our diet may never be the same.”¹⁰
In our own day, the American Heart Association continues to promote the hypothesis with vigor. In 2009, it updated its official stance, recommending at least 5 to 10 percent of calories as omega-6 PUFA with additional PUFA coming from omega-3 sources, and concluded that intakes even higher than this “appear to be safe and may be even more beneficial (as part of a low-saturated fat, low-cholesterol diet).”¹¹ It was one thing to promote this hypothesis in 1961 when it had never been tested, but to throw a PUFA party in 2009 and suggest we all wash away our cardiovascular concerns with swigs of soybean oil is to ignore with callow abandon all the lessons we have learned from clinical trials published in the intervening decades.

Six randomized, controlled trials specifically testing the effect of the substitution of polyunsaturated vegetable oils for animal fats on heart disease have been published.^12-17 These trials were all published between 1965 and 1989. Two of them found that vegetable oils increased the risk of heart disease,^{12, 14} although one of these creatively concluded from this that “men who have had myocardial infarction are not a good choice for testing the lipid hypothesis.”¹⁴ Two of them reported no effect of vegetable oil.^{13, 15} The authors of one of these two trials, however, only reported the results half-way through the study.¹⁵ In the final report, they pooled the two groups together and compared them to a new control group that had not received any dietary advice at all.¹⁸ As a result, we have no way of knowing the true effect of vegetable oil in that study. Two of the six trials were double-blind, and deserve special attention.^{16, 17} These are the Minnesota Coronary Survey and the Los Angeles Veterans Administration Hospital Study.

The Minnesota Coronary Survey tested the effect of substituting vegetable oils for animal fats in hospital patients who were on the diets for an average duration of only one year.¹⁶ As shown in Figure 2, vegetable oil had no effect on cardiovascular disease. While its effect on total mortality was not statistically significant, however, total survival was nevertheless better in the group eating saturated fat. We naturally must wonder what would have happened to total mortality had the subjects been on the diets for longer than one year.

The Los Angeles Veterans Administration Hospital Study lasted over eight years, and most of the subjects were enrolled for at least six years.¹⁷ It is the only one of these six studies where the mean age of the subjects was greater than sixty, so it allows us to better see the effect of vegetable oils on the risk of cancer, if such an effect exists.

Subjects eating the diet rich in vegetable oils had a lower risk of cardiovascular mortality, but a higher risk of mortality from other causes. As a result, diet had no effect on total mortality. This is clearly shown in Figure 3. As shown in Figure 4, deaths from cancer began to increase in the vegetable oil group after two years, and the increase became much larger after five years.¹⁹ As shown in Figure 5, the difference in the incidence of all deaths from non-cardiovascular causes began to increase in the vegetable oil group only after four years and remained extremely small until seven years.¹⁷ After seven years, non-cardiovascular mortality began to increase rapidly. The disturbing possibility that the true harms of vegetable oils take years to emerge did not escape the authors, and they concluded that “future clinical trials of diets rich in unsaturated fat must be planned for periods well in excess of eight years, rather than for the five-year periods that have been the usual goal.” Such longer trials have never been conducted.

Although a superficial analysis of this study would suggest that vegetable oils decrease the risk of heart disease while increasing the risk of cancer and other diseases, this may not be the case. Even though the investigators randomly allocated the subjects to each group, the randomization failed to equally balance rates of smoking between the two groups. There were twice as many heavy smokers and 60 percent more moderate smokers in the group consuming traditional animal fats, while there were more light smokers and non-smokers in the group consuming vegetable oils.¹⁷ The diet rich in animal fats, moreover, was deficient in vitamin E. Animal experiments suggest that we should obtain 0.6 milligrams of vitamin E for every gram of PUFA we consume. The vegetable oil diet came close to this requirement, supplying a ratio of over 0.5, but the animal fat diet fell miserably short of it, supplying a ratio of less than 0.2.²⁰

Animal fats are not intrinsically deficient in vitamin E, however. The average store-bought butter, for example, easily meets the vitamin E requirement, and a high-quality pastured butter can provide more than double this requirement. ^21,22 It is thus unclear why the animal fat diet was so deficient in the vitamin, but this deficiency in combination with the higher rate of smoking may have contributed to the greater risk of cardiovascular disease in the animal fat group.

It appears from these studies, then, that vegetable oils promote cancer while animal fats protect against it even in the presence of smoking and vitamin E deficiency. Vegetable oils may promote heart disease as occurred in two studies,^{12, 14} but the results of the LA Veterans Administration Hospital Study make this unclear. The authors of this study themselves concluded as follows: “. . . we consider our own trial, with or without the support of other published data, to have fallen short of providing a definitive and final answer concerning dietary prevention of heart disease.”

These studies leave many questions to be answered. Are the effects of vegetable oils with different proportions of omega-6 and omega-3 fatty acids different from one another? What is the effect of vegetable oils over a lifetime, beginning in youth? Are there certain dietary contexts that make vegetable oils harmful, and others that make them safe? The larger question, however, is whether, given all this uncertainty, we should make ourselves guinea pigs for these newfangled foods. No one has yet offered a better summary of the issue than that offered by the late endocrinologist Broda Barnes in his 1976 book, Solved: The Riddle of Heart Attacks:
Everyone should have the privilege of playing Russian Roulette if it is desired, but it is only fair to have the warning that with the use of polyunsaturated fats the gun probably contains live ammunition.²³

MYTH 2: ARACHIDONIC ACID IS A "BAD FAT"

The second myth is that animal fats promote inflammation because they contain a small amount of the omega-6 PUFA arachidonic acid, found primarily in liver and egg yolks with smaller amounts in butter and meat fats. This hypothesis emerged in the scientific literature in the 1980s and 1990s as researchers began attributing the low rate of heart disease among traditional Inuit to their consumption of large amounts of omega-3 fatty acids from marine oils.²⁴ Researchers argued that these omega-3 fatty acids were protective precisely because they counteracted the inflammatory effects of arachidonic acid. Barry Sears popularized this idea in his best-selling 1995 book The Zone Diet.²⁵ Therein, he proclaimed excess arachidonic acid “your worst biological nightmare.” Not only is it inflammatory, he wrote, but it “is so potent and so dangerous that when you inject it into the bloodstream of rabbits the animals die within three minutes.”

Despite these sensational claims, arachidonic acid is not inherently inflammatory. Its deficiency, in fact, produces a number of inflammatory symptoms, including dandruff, hair loss, infertility and irritated, red, sore, swollen, and scaly skin.^26,27 Inhibiting supposedly “inflammatory” products made from arachidonic acid such as prostaglandin E2 using over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs) can produce a number of inflammatory outcomes. These drugs induce intestinal pathologies that closely resemble celiac disease in laboratory animals in response to gluten or even egg white,^28,29 and they interfere with the resolution of autoimmune conditions.³⁰

Although it is true that our bodies use arachidonic acid to initiate inflammation—a vital process if we want to survive to adulthood without being wiped out by pathogenic microbes —our bodies also use this fatty acid to suppress inflammation or to resolve inflammation once it has run its course. We use arachidonic acid to make cell-to-cell junctions that form physical barriers against toxins and pathogens,^31-33 to create a unique environment in the gut that causes our immune system to react to food proteins with tolerance instead of intolerance,³⁴ and to make important molecules called lipoxins that help resolve existing inflammation.30,35 We even use arachidonic acid to signal the conversion of omega-3 fatty acids to resolvins, another class of molecules that help resolve inflammation.³⁰ It makes little sense to characterize this fatty acid as singularly inflammatory in nature when it has so many anti-inflammatory functions, and when it is present in so many traditional foods consumed by populations free of inflammatory diseases.

MYTH 3: SOLID FATS = EMPTY CALORIES

The third myth, that “solid fats” are empty calories with no nutritional value, has emerged more recently with the latest revision of the USDA’s Dietary Guidelines for Americans. This document defines a “nutrient-dense” food as one whose “nutrients and other beneficial substances . . . have not been 'diluted' by the addition of calories from added solid fats, added sugars, or added refined starches, or by the solid fats naturally present in the food.”³⁶ This peculiar definition of “nutrient-dense” allows the addition of liquid oils but requires the removal of natural solid fats. “Solid fats” are defined as “fats with a high content of saturated and/or trans fatty acids, which are usually solid at room temperature.” Using this definition, one could ostensibly make milk more “nutrient-dense” by replacing its natural butterfat with corn oil.

The natural fats present in foods carry all of their fat-soluble vitamins, and added fats further increase their bioavailability. Human trials, for example, have clearly shown that butterfat increases the absorption of vitamin E,³⁷ and that canola oil increases the absorption of carotenoids from salad.³⁸ The more fat one adds, according to these studies, the greater the absorption of fatsoluble nutrients. This can hardly be considered a decrease in nutrient density!

Animal experiments, moreover, suggest that fats and oils low in PUFA provide the best absorption of fat-soluble nutrients. When compared to corn oil, for example, olive oil roughly doubles the absorption of lycopene and astaxanthin in rats.³⁹ If the lower absorption seen with corn oil is a result of its higher PUFA content, then socalled “solid fats” might prove superior even to olive oil, and certainly to canola oil.

THE TRUTH SHALL SET US FREE

Clinical trials have failed miserably to support the hypothesis that replacing saturated animal fats with polyunsaturated vegetable oils would prevent heart disease. They have shown instead that vegetable oils likely promote cancer and perhaps even heart disease. Arachidonic acid in animal fat is not "deadly," but is necessary for our bodies to initiate, suppress, or resolve inflammation as needed. These are all vital processes that allow us to respond appropriately to our environment. “Solid fats” do not “dilute” the nutrient density of our food. On the contrary, they carry fat-soluble nutrients and provide for their absorption.

When we observe the ease with which these myths arise and the vigor with which they are promulgated to the public, it is important for us not to create our own equal and opposite myths. We should keep in mind that traditional diets varied widely in their fat and carbohydrate contents. Nutritional needs vary from person to person, and from one stage of life to another. Any health-promoting component of the diet, including animal fat, can become harmful if it displaces other health-promoting components. It is thus entirely plausible that some people under some circumstances may benefit by reducing their intakes of animal fat and increasing their intakes of other traditional foods. We should thus beware of promoting any “correct” amount of animal fat to consume. We should instead look upon the earth’s menu of natural, traditional foods without fear, and choose those foods we need and enjoy in freedom.

REFERENCES
1. Lindeberg S, et al. Age relations of cardiovascular risk factors in a traditional Melanesian society: the Kitava study. Am J Clin Nutr. 1997;66(4):845-52.
2. Prior IA, et al. Cholesterol, coconuts, and diet on Polynesian atolls: a natural experiment: the Pukapuka and Tokelau island studies. Am J Clin Nutr. 1981;34(8):1552-61.
3. USDA Agricultural Research Service.What We Eat in America, NHANES 2007-2008. Table 5. Energy Intakes: Percentages of Energy from Protein, Carbohydrate, Fat, and Alcohol, by Gender and Age, in the United States, 2007- 2008 http://www.ars.usda.gov/SP2UserFiles/Place/12355000/pdf/0708/Table_5_EIN_GEN_07.pdf Accessed December 29, 2011.
4. Keys A. Atherosclerosis: a problem in newer public health. J Mt Sinai Hosp NY. 1953;20(2):118-39.
5. Kinsell LW, et al. Dietary modification of serum cholesterol and phospholipid levels. J Clin Endocrinol. Metab. 1952;12(7):909-13.
6. Ahrens EH Jr., et al..Effect on human serum lipids of substituting plant for animal fat in diet. Proc Soc Exp Biol Med. 1954;86(4):872-8.
7. Page IH, et al. Atherosclerosis and the Fat Content of the Diet. Circulation. 1957;16:163-178.
8. Dietary fat and its relation to heart attacks and strokes: report by the Central Committee for Medical and Community Program of the AHA. 1961;23:133-6.
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10. Wallis C, Crook C, Delaney P, Gribben S. Hold the Eggs and Butter. Time magazine. March 26, 1984.
11. Harris WS, et al. Omega-6 fatty acids and risk for cardiovascular disease: a science advisory from the AHA Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 2009;119(6):902- 7.
12. Rose GA, et al. Corn oil in treatment of ischaemic heart disease. Br Med J. Jun 12 1965;1(5449):1531- 1533.
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14. Woodhill JM, et al. Low fat, low cholesterol diet in secondary prevention of CHD. Adv Exp Med Biol. 1978;109:317-330.
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This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly magazine of the Weston A. Price Foundation, Spring 2012.
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Read the full article here.

Credible Evidence

FB-TW

Saturday, June 8, 2013

Dietary Fats and Health - Lawrence

Dietary Fats and Health: Dietary Recommendations in the Context of Scientific Evidence¹

Abstract

Introduction

Dietary fatty acids and serum cholesterol

Genetic factors

Fatty acids involved in atherogenesis and CVD

Lipid peroxidation and inflammation

Are low-fat, low-saturated fat diets healthier?

Less fat generally means more carbohydrate

Conclusions

Acknowledgments

Footnotes

Monday, May 20, 2013

Dietary Fats and Health - Lawrence

Dietary Fats and Health

Abstract

Thursday, September 13, 2012

Association Between Omega-3 Fatty Acid Supplementation & Risk of Major Cardiovasular Disease - Harris

Positve view of the study

First negative view about the study

Second negative view about the sudy

Friday, August 17, 2012

High fat diet during pregnancy leads to severe liver disease - Kresser

More silly shenanigans against saturated fat

Friday, August 3, 2012

Liver saving saturated fats

Liver saving saturated fats

Sunday, March 25, 2012

Good Fats, Bad Fats: Separating Fact from Fiction

Good Fats, Bad Fats: Separating Fact from Fiction

MYTH 1: SATURATED FAT IS BAD, POLYUNSATURATED FAT IS GOOD

MYTH 2: ARACHIDONIC ACID IS A "BAD FAT"

MYTH 3: SOLID FATS = EMPTY CALORIES

THE TRUTH SHALL SET US FREE

FB-TW

Saturday, June 8, 2013

Dietary Fats and Health: Dietary Recommendations in the Context of Scientific Evidence1

Abstract

Introduction

Dietary fatty acids and serum cholesterol

Genetic factors

Fatty acids involved in atherogenesis and CVD

Lipid peroxidation and inflammation

Are low-fat, low-saturated fat diets healthier?

Less fat generally means more carbohydrate

Conclusions

Acknowledgments

Footnotes

Monday, May 20, 2013

Abstract

Thursday, September 13, 2012

Positve view of the study

First negative view about the study

Second negative view about the sudy

Friday, August 17, 2012

Friday, August 3, 2012

Sunday, March 25, 2012

MYTH 1: SATURATED FAT IS BAD, POLYUNSATURATED FAT IS GOOD

MYTH 2: ARACHIDONIC ACID IS A "BAD FAT"

MYTH 3: SOLID FATS = EMPTY CALORIES

THE TRUTH SHALL SET US FREE

Dietary Fats and Health: Dietary Recommendations in the Context of Scientific Evidence¹