SATURATED FATTY ACIDS
The early studies of Keys (22) and Hegsted(17), as well as several recent investigations(15), have demonstrated the importance of dietary fatty acids in the regulation of blood cholesterol levels. The predominant long chain saturated fatty acids of varying chain length in food include lauric acid (12:0) myristic acid, (14:0) palmitic acid (16:0), and stearic acid(18:0). Medium chain fatty acids (8:0-10:0), often used in parenteral nutrition because they are normally absorbed directly into the hepatic portal system, were thought to be neutral, e.g., neither raising nor lowering blood cholesterol levels. However, in a recent study reported by Cater et al.(5), this notion has been questioned. Briefly, the study conducted in nine mildly hypercholesterolemic men demonstrated that total cholesterol (TC) concentrations in participants fed medium chain triglycerides(MCT) were similar to those in men fed palm oil and 13% higher than in the group fed high oleic sunflower oil. On the basis of the study, the authors suggested that medium chain fatty acids were about half as potent as palmitic acid in raising TC and low density lipoprotein cholesterol (LDL-C) concentrations. These human studies of the potency of medium chain fatty acids are in disagreement with one study in hamsters (62), which found that MCT produced a cholesterolemia similar to a high carbohydrate/low fat diet, leading the authors to conclude that MCT were neutral. On the other hand, a preliminary study in hamsters found MCT to be as atherogenic as saturated fat (41).
There have been numerous human studies of long chain saturated fatty acid effects (12:0-18:0) on blood cholesterol levels. The early studies of Keys(22) and Hegsted (17) indicated that the predominant cholesterolraising fatty acids were 12:0, 14:0, and 16:0, and that 18:0 stearic acid was neutral. These early studies and the recent investigations (7), such as described inFigure 1, suggest that the order of potency for cholesterol raising fatty acids was 14:0>16:0>12:0. Despite the greater potency of myristic acid, palmitic acid is of more concern because of its greater intake relative to other fatty acids.
The neutrality of 18:0, stearic acid, was first postulated by Keys(22) and Hegsted (17) and has been supported by recent studies (3,64). Explanations for the neutrality of stearic acid include its desaturation to oleic acid (18:1), a monounsaturated fatty acid with cholesterol lowering properties (see below).
Animal studies of the effect of specific saturated fatty acids on cholesterolemia have provided us with not only support, in general, for the human studies but also mechanism(s) of action. In studies conducted by Woollett et al. (62) Golden Syrian hamsters were fed specially prepared triglycerides made up of single fatty acids of chain length from 6:0 to 18:0. These studies demonstrated that relative to a control diet of 10% olive oil and 0.12% cholesterol (wt·wt-1), the intake of dietary triglycerides enriched in 6:0, 8:0, and 10:0 fatty acids did not raise plasma LDL-C levels (Fig. 2) and had no effect on hepatic LDL receptor activity (Fig. 3) or LDL cholesterol production (Fig. 4). In other words, they were neutral. On the other hand, feeding triglycerides containing either 12:0, 14:0, or 16:0 fatty acids increased plasma LDL-C nearly two-fold (Fig. 2), decreased hepatic LDL receptor activity (Fig. 3), and increased LDL cholesterol production rates (Fig. 4) relative to the control diet. The 18:0-enriched triglycerides did not alter hepatic LDL receptor activity or LDL cholesterol production rate and therefore did not affect plasma LDL-C levels. While the exact mechanism(s) to explain these differential fatty acid chain length effects is uncertain, it has been hypothesized that 6:0, 8:0, and 10:0 fatty acids are rapidly absorbed into the hepatic portal circulation where they are metabolized to acetyl CoA which do not alter plasma LDL-C levels. In contrast, the 12:0, 14:0, and 16:0 enriched triglycerides result in accumulation of these fatty acids in the liver and, in the process, possibly by manipulating hepatic sterol pools or membrane fluidity, alter hepatic LDL receptor activity and/or production rates. The explanation for the lack of effect of 18:0 is not known with any certainty.
SATURATED VEGETABLE OILS
While the studies of the effects of specific saturated fatty acids on cholesterolemia have been limited in both human and animal studies, numerous investigations have used different saturated whole vegetable oils. The studies of Fernandez et al. (10) in the guinea pig revealed that plasma TC and LDL-C levels were highest for the palm kernel oil (PK)-fed animals followed by palm oil (PO) and then beef tallow (BT). Explanation(s) for these changes included reduced LDL fractional catabolic rate (FCR) and LDL receptor number (PK<PO<BT).
A study in cynomolgus monkeys fed either the very saturated vegetable oil, coconut oil (46% laurate + 19% myristate + 20% palmitate), or an oil blend(OB) (5% myristate + 20% palmitate) found comparable levels of plasma LDL-C and apo B between the two diet treatments, as well as similar LDL metabolic processes (48). Similarly, studies in the hamster by Woollett et al. (61) found that hydrogenated coconut oil(HCO) raised plasma LDL-C levels higher than MCT, and these results were associated with decreases in hepatic LDL receptor activity and increased LDL production rate of the HCO-fed animals relative to the MCT group. In general, the human studies support the hypercholesterolemic responses of these tropical oils (coconut oil, palm kernel oil, and palm oil).
UNSATURATED VEGETABLE OILS
The initial studies of Keys (22) and Hegsted(17) have described the cholesterol lowering properties of polyunsaturated vegetable oils. Since then, several articles have reviewed the cholesterolemic response of polyunsaturated vegetable oils enriched in linoleic acid (18:2) when replacing saturated fat in the diet(13,14,28,30,32,46). Several of these articles have described predictive equations for the expected degree of cholesterol lowering when replacing saturated fat with polyunsaturated fat. In general, polyunsaturated fats are half as effective in lowering cholesterol levels as saturated fats are in raising cholesterol levels.
Vegetable oils enriched in monounsaturated fatty acids (MUFA) such as oleic acid (18:1) were once considered neutral (28). However, recent clinical studies in humans(13,14,30,32,34,46) and experimental studies in animals(4,14,19,47,63) indicate that dietary triglycerides enriched in oleic acids do lower blood TC and LDL-C levels when replacing diets enriched in saturated fatty acids.
Numerous animal studies have investigated the mechanism(s) of the cholesterol-lowering properties of unsaturated vegetable oils.
Studies by Spady and Dietschy (47) in Golden Syrian hamsters demonstrated that when the saturated fat, hydrogenated coconut oil(HCO) was replaced by the polyunsaturated fat (PUFA), safflower oil, and/or the MUFA oil olive oil, the 61% and 50% decrease in LDL-C, respectively, was associated with an average 192% increase in hepatic LDL clearance. Horton et al. (19), from the same group of investigators, demonstrated that the PUFA-induced increase in hepatic LDL receptor activity was associated with a two-fold elevation in hepatic LDL receptor mRNA. This increase of LDL receptor activity by unsaturated fats, at the transcription level in rodents, is in agreemnt with studies in nonhuman primates such as cebus monkeys fed corn oil versus coconut oil (18), or baboons fed the saturated fat coconut oil versus peanut or olive oil as the MUFA, and corn oil as the PUFA (12,26).
Studies by Fernandez et al. (11) in guinea pigs fed the saturated fat lard versus the PUFA corn oil showed that the decrease in plasma LDL-C in PUFA-fed animals was associated with an increase in LDL receptor number, greater LDL receptor activity, and less LDL flux rates. Surprisingly, in the guinea pig, MUFA-feeding was not associated with decreased plasma LDL-C relative to a high SFA diet (11). These PUFA-induced diet effects on plasma LDL-C in rodents and the associated changes in LDL receptor number, LDL fractional catabolic rate (FCR), and LDL production rate have been supported by studies in nonhuman primates. For example, studies in male cebus monkeys (40) showed that replacing the saturated fat coconut oil with the PUFA corn oil reduced plasma LDL-C levels, and this finding was associated with increased LDL FCR. Similarly, studies in male cynomolgus monkeys (4) showed that replacing a high saturated fat diet (coconut oil and butter) with either a MUFA diet (olive oil and canola oil) or PUFA diet (corn oil and safflower oil) reduced plasma LDL-C, and these changes were associated with increased LDL FCR and decreased LDL production rate. Another study in African green monkeys fed a typical Western diet (47% kcal as fat, polyunsaturated/saturated(P/S = 0.3) versus a prudent diet (PD) (29% kcal as fat, P/S = 2.0), reduced plasma LDL in PD fed monkeys, and this decrease was associated with both an increase in LDL FCR and decrease in LDL production rate in PD-fed monkeys(57).
TRANS FATTY ACIDS
Dietary fat recommendations from various public health agencies include reducing total fat intake from the current 34-36% of calories to <30% calories and reducing saturated fat intake from 12-14% of calories to <10% calories. Substituting oils rich in PUFA's and MUFA's for saturated fat is also prescribed.
Hydrogenation of vegetable oils for use in frying, baking, and spreads reduces the need for cholesterolraising tropical oils such as coconut and palm oil.
Most naturally occurring unsaturated fats have the (cis) configuration, i.e., hydrogens are located on the same side of the double bond. However, during hydrogenation a chemical change occurs to some fatty acid molecules which moves the hydrogens to opposite sides of the double bond(Fig. 5). These new fatty acids are called“trans” fatty acids, the major one being the trans form of oleic acid called elaidic acid or trans 18:1. Trans fatty acids also occur naturally in meats and dairy products, the major form being trans form of palmitic acid or trans 16:1. While assessments of trans fatty acid intake are highly variable, estimates indicate that they make up only 2-4% of total energy in U.S. diets, significantly less than our intake of saturated fat (12-14%)
The effect of trans fatty acids on blood cholesterol levels have been researched for over 20 yr. The earlier studies(29,53,54) suggested that cis and trans fatty acids did not affect blood cholesterol levels differently. In contrast, recent studies(21,27,32,37,38,58,59,65) suggest that trans 18:1, fed predominantly as hydrogenated margarine may independently raise plasma LDL-C levels. However, a recent letter to the editor (39) and review of the evidence of trans fatty acids and coronary heart disease risk (9) have taken issue with interpretation of these clinical trials. For example, from the recent meta-analysis of Mensink and Katan (34) and Yu et al.(64), it appears that both oleate and linoleate intake reduce plasma TC and LDL-C levels. Thus, clinical trials cited above(21,27,33,37,38,58,59,65), which add trans fatty acids at the expense of either cis oleate or linoleate, make it nearly impossible to differentiate whether the addition of trans fatty acids independently raises TC and LDL-C or whether these changes are the result of removal of the cholesterol lowering oleate and linoleate from the diet. Thus, in the studies of Mensink and Katan (33), the increased concentrations of blood TC (6%) and LDL cholesterol (14%) in individuals fed the trans fatty acid-containing diet relative to the oleate diet were not only associated with an increase in the content of the trans fatty acids (from 0% to 11% of energy) but also a 45% decrease in oleate content. Similarly, in the study by Nestel et al. (37), the increased concentrations of blood TC (7%) and LDL-C cholesterol (9%) in individuals consuming the trans fatty acid diet were not only associated with an increase in the content of dietary trans fatty acid (from 1% to 6% of energy) but also with a 17% decrease in oleate content. In the recent study by Judd et al. (21), the addition of moderate amounts of trans fatty acids (4% of energy) and high amounts (7% of energy) to a diet fed for 6 wk raised concentrations of TC and LDL-C 4% and 6%, respectively, with the moderate diet and 5% and 8%, respectively, with the high trans fatty acid diet. But once again, trans fatty acids in the diet were added at the expense of a 35% reduction in oleate content in the high trans fatty acid diet. In the recent study by Lichtenstein et al. (27), the hydrogenation of corn oil resulted in an increase in concentrations of TC (6%) and LDL-C cholesterol (8%). However, although hydrogenation increased dietary trans fatty acid levels (from 0.4% to 4%), this diet also contained 5% more cholesterolraising fatty acids and 22% and 12% less oleate and polyunsaturates, respectively. Finally, in another human study by Zock and Katan (65), relative to a linoleate-enriched diet the trans fatty acid diet increased concentrations of TC (3%) and LDL-C (8%). However, the trans fatty acid-enriched diet had 68% less linoleate relative to the linoleate diet. In addition, in this same study of the comparison between the trans fatty acid and stearate diet, in which the amounts of dietary oleate and linoleate were virtually identical, the addition of trans fatty acids did not result in any significant increase in concentrations of total cholesterol and LDL cholesterol. Thus, these results suggest that the cholesterolemic effects of trans fatty acids and stearate are equal, and, if the latter is considered to be biologically neutral, it would follow that the former is neutral also. The issue of whether trans fatty acids reduce HDL-C or increase Lp(a) is equivocal, as there are studies that show either a positive effect(33,65) or no effect(21,27) for HDL-C and, similarly, a positive effect(35,37) or no effect(6,27) for blood Lp(a) levels.
A recent hamster study by Woollett et al. (60) supports the neutrality of trans oleate. The authors found that trans-oleate ingestion produced (a) similar plasma LDL-C levels to 8:0 and 18:0 fatty acids, (b) lower plasma LDL-C levels than myristate, and (c) greater plasma LDL-C levels than cis oleate. The comparative neutrality of 8:0, 18:0, and trans 18:1 in terms of plasma LDL-C level was largely explained by the negligible impact that these fatty acids had on hepatic sterol pools and similarly hepatic clearance and production of LDL-C.
Similarly, there is questionable interpretation of epidemiological evidence as well. For example, one might expect a dose-dependent effect of trans fatty acid intake in cardiovascular disease risk, i.e., the more you consume, the higher the risk. However, as one can see from Figure 6 in Ascherio et al. (2), the relative risk moving from the first to the fifth quintile was 1.0, 0.8, 0.4, 0.7, and 2.0, suggesting a protective effect of trans fatty acid intake at the 3rd quintile. Also, in studies comparing concentrations of specific trans fatty acids in case and control studies of individuals who died of myocardial infarcts (MI) or cardiac arrest, the trans association was with trans 16:1 and not trans 18:1(16,45,49-51). In addition, the risk of MI was either not associated with trans 18:1 intake(1) or was lower with trans 18:1 intake(43). Finally, numerous earlier studies in rabbits, pigs, and monkeys,(8,20,23-25,31,36,42,44,52,55,56) and one recent study in hamsters (41), have suggested no increased development of atherosclerosis with consumption of trans containing vegetable oils compared with their nonhydrogenated vegetable oil counterpart.
In summary, the cholesterol-raising saturated fatty acids are 12:0, 14:0, and 16:0. Stearic acid (18:0) appears to be neutral. MCT's may not be neutral as evidenced by a recent study in humans. The fatty acids, 12:0, 14:0, and 16:0 raise plasma LDL-C levels by decreasing hepatic LDL clearance and increasing LDL production rate. Why 18:0 is neutral remains to be elucidated. Unsaturated vegetable oils enriched in PUFA's and MUFA's both lower plasma LDL-C when replacing saturated fat in the diet. The mechanism(s) responsible for the LDL-C reduction with PUFA and MUFA diets is largely explained by increased hepatic LDL FCR. Hydrogenation of vegetable oils produce trans fatty acids. Recent evidence in humans suggest that trans fatty acids raise LDL-C levels, but study design does not permit one to determine whether this is an effect independent of the removal of cholesterol-lowering cis linoleate or oleate. In any case, plasma LDL-C levels are still lower in individuals consuming hydrogenated vegetable compared with what they were designed to replace, i.e., animal fat and tropical oils. Case studies in human and animal studies do not show increased heart disease or atherosclerosis with trans fatty acid consumption.
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