• Introduction
  
  
• The specific dietary context in which fat and the other macronutrients occur is key, but often overlooked.
  
  
• Saturated/unsaturated fat composition of wild animal tissues, and consumption levels in modern vs. pre-agricultural peoples.
  
  
• Limitation of the Keys equation in predicting expected serum cholesterol levels from fat and cholesterol in the diet.
  
  
• Clarification of the role of saturated fats in promoting high cholesterol.
  
  
• The role of essential fatty acids (EFAs) and the balance of omega-6 to omega-3 fats.
  
  
• Effect of fat, protein, and carbohydrate on glucagon levels.
  
  
• Protein levels and their effect on blood lipids.
  
  
• Low-carbohydrate diets by themselves do not eliminate the cholesterol-raising effects of high-saturated-fat diets.
  
  
• Glycemic response of fat combined with carbohydrate.
  
  
• What is the relevance of genetic differences in individual blood lipid response to high and low-fat diets?.
  
  
• Conclusion
  
  
• REFERENCES

Introduction

Conventional wisdom about macronutrient ratios challenged in last decade. The conventional wisdom of orthodox nutritionists for the past 20-25 years regarding macronutrient intake has been that a high-carbohydrate, low-fat diet is the optimal diet for humans and benefits virtually all pathological conditions ranging from heart disease to cancer. In the past 10-12 years, however, this concept has been seriously questioned in terms of deleterious changes (elevated triglycerides and VLDL, and lowered HDL) which occur in blood-lipid profiles from such advice. Increasingly, influential scientists (Scott Grundy, Walter Willett, Gerald Reaven) and institutions (Harvard School of Public Health) have recognized this shortcoming of high-carb, low-fat diets, and are now recommending monounsaturated fat in lieu of carbohydrate [Grundy 1986; Mensink et al. 1987].

Despite the thousands--perhaps tens of thousands--of clinical trials which have been conducted manipulating the macronutrient (protein, carbohydrate, and fat) content of diet, however, there are perhaps no more than a half-dozen which have examined the influence of a high-protein, low-carbohydrate diet (with varying fat levels) upon human health and metabolism. This is somewhat ironic, in that this macronutrient pattern appears to be the one which nourished humankind (members of the genus Homo) for all of our time (2.5 million years) on this planet, except for the last 10,000 years since the advent of grain-based agriculture.

The specific dietary context in which fat and the other macronutrients occur is key, but often overlooked

There is little doubt that Paleolithic man consumed (probably preferentially) the fatty portions of wild game animals. During certain times of the year (late summer and early fall) the total lipid content of large herbivorous animals was considerable, and at these times saturated fat consumption could have been high. At other times, however, it would have been modest (except perhaps for high-latitude peoples who were the most dependent on animal meat due to a colder climate less hospitable to plant life), even while the overall yearly consumption of all forms of fat could have been relatively high. However, despite the consumption of a largely animal-based diet that at times can include a high overall level of fats, most modern-day hunter-gatherers exhibit low serum cholesterol levels, low blood pressure, and low to non-existent mortality rates from coronary heart disease (CHD) [Eaton 1988; Bang and Dyerberg 1980; Leonard et al. 1994].

At first, this data seems paradoxical in light of the almost universal recommendations of a low-fat, high-carbohydrate diet in the treatment of CHD. However, there are important and subtle differences between the high-fat/animal-based diets of pre-agricultural man and the high-fat diets of modern man which can account for this paradoxical situation:

• Differences in trans fats and oxidation of cholesterol. There is increasing recognition that for the atherosclerotic process to occur, there must not only be elevated levels of LDL cholesterol, but that the lipids and cholesterol carried by LDL must be oxidized [Steinberg et al. 1989]. The macrophages which take up oxidized LDL molecules and eventually become the foam cells of the atherosclerotic plaque have a scavenger receptor which is different from native LDL receptors and which does not down-regulate. Consequently, continually elevated levels of oxidized LDL in the plasma tends to promote the atherosclerotic process.

  High levels of dietary linoleate increase LDL oxidizability ([Louheranta et al. 1996]. Because refined vegetable oils were not present in pre-agricultural diets, the linoleate levels would have been lower than in Western diets, wherein the vegetable fat consumption has increased 300% since 1910 and the animal-fat consumption has decreased slightly [ASCN/AIN Task Force 1996]. Thus the relatively high levels of vegetable oils consumed in the Western diet, along with relatively high levels of saturated fats, promote a lipid profile in which LDL cholesterol is elevated and more prone to oxidation and hence to the development of CHD.

• Differences in protein intake levels. The protein content of the paleolithic diet was significantly higher than the average 12-15% of the Western diet. Recent studies [Wolfe 1995; Wolfe et al. 1991] show that isocaloric (calorie-for-calorie) replacement of carbohydrate with protein lowers total cholesterol, LDL, VLDL, and triglycerides (TG) while elevating HDL cholesterol--all of which are favorable responses in terms of blood-lipid levels. Consequently, a high dietary protein content even in the face of increasing overall fats, or increasing saturated fat, serves to lower serum cholesterol levels and reduce the risk for CHD.

• Differences in carbohydrate intake. The carbohydrate content of pre-agricultural diets was generally lower than the 45-55% of the Western diet. Consequently, the post-prandial (after-meal) lipemic excursions (changes in blood lipid levels)--during which LDL molecules are most prone to oxidation--would have been reduced, since the addition of carbohydrate to a fat-rich meal exacerbates this swing [Chen et al. 1992]. Pre-agricultural eating patterns show that fat and protein were generally eaten together, whereas carbohydrate meals were eaten separately. This eating pattern would have reduced post-prandial lipemic excursions. Additionally, the reduced carbohydrate content of pre-agricultural diets would have improved the portions of the blood-lipid profile (TG, VLDL, HDL, Lp(a)) which are worsened by high-carbohydrate diets [Reaven 1995].

• Differences in fatty-acid intake profiles. Work from our laboratory [Cordain et al. 1998], as well as that of others, has shown that the fatty-acid profiles of storage as well as structural fat are quite different when contrasting wild to domesticated animals. Of the dietary saturated fats, 12:0, 14:0, and 16:0 are known to elevate plasma cholesterol levels, whereas 18:0 is neutral or perhaps hypocholesterolemic (cholesterol-lowering). The saturated fat of bone marrow and depot fat in wild animals contains greater levels of 18:0 and lower levels of 14:0 and 16:0 when compared to domestic animals.

  Additionally, the structural (e.g., polyunsaturated) lipid content in game meat is also quite different than that in domestic meat. There generally are higher levels of all n3 ("omega 3") fats and higher levels of all 20 and 22-carbon fats of both the n3 and n6 ("omega 6") varieties in game meat. The n6/n3 ratio of beef averages about 15, whereas in wild animals it is about 4-5. Again, higher levels of n6 lipids in domestic animals, particularly linoleate, tend to increase LDL oxidizability, whereas the higher levels of n3 fats in game animals are cardio-protective.

  Consequently, the consumption of saturated fats in pre-agricultural diets occurred against a background of dietary lipids which was much different than the background fats in the modern diet. Recent evidence clearly shows that the composition of fatty acids in a meal can improve serum lipid values despite widely varying fat levels [Nelson et al. 1995].

• Absence of dairy fats. Pre-agricultural diets by definition would not have included dairy fats. In modern Western diets, about a third of the saturated fat is contributed by dairy foods (milk, butter, cheese, ice cream). In metabolic ward studies, butter fat raised LDL cholesterol levels significantly higher than beef tallow [Denke and Grundy 1991]. Further, milk consumption is the best worldwide predictor of CHD mortality of all dietary elements [Artaud-Wild et al. 1993]. Bovine milk fat is quite low in the long-chain cardio-protective n3 fats, and has a high n6 ratio. Additionally the calcium to magnesium (Ca/Mg) ratio in milk and dairy products is quite high compared to the average 1:1 ratio in foods available to pre-agricultural man. Elevated Ca/Mg ratios have been shown to be positively related to CHD [Varo 1974]. This data suggests dairy products would be quite atherogenic, particularly when consumed in a background of other dietary elements in the Western diet.

• Large disparity in activity levels. Modern man eating a high-fat diet is generally quite inactive compared to pre-agricultural man [Cordain, Gotshall, and Eaton 1997]. High levels of activity serve to improve insulin sensitivity and lower TG and VLDL while increasing HDL cholesterol.

One final comment: Not only does the high sodium content of the Western diet predispose us to hypertension, osteoporosis, urinary tract stones, menierre's syndrome, stomach cancer, insomnia, asthma and initiation and promotion of all types of cancer, it also seems to do the same in our closest relative, the chimp [Denton et al. 1995].

Saturated/unsaturated fat composition of wild animal tissues, and consumption levels in modern vs. pre-agricultural peoples

Our data on the fatty-acid distribution in tissues of wild animals presented at a recent conference on the return of n3 fats to the food supply, held at the National Institutes of Health in Bethesda, Maryland has been recently published in World Review of Nutrition and Dietetics. [Cordain et al. 1998]. This data refutes contentions made by some that the overall PUFA in wild-animal tissues is low. To the contrary, it is relatively high in both brain (26%) and muscle (36%) as our data shows, and which corroborates earlier work of Crawford et al. [1969].

The difference in polyunsaturated fatty acids (PUFAs) between the Western diet and the so-called "paleolithic diet" is that the PUFAs in the Western diet are predominantly based upon 18-carbon lipids (vegetable oils) with huge amounts of 18:2n6 (linoleic acid) predominating. The PUFA content of the paleolithic diet is higher than that of the Western diet (19.2% vs. 12.7% [Bang and Dyerberg 1980]) with much higher levels of HUFA (>20-carbon lipids) of both the n6 and n3 families.

Once again, it should be emphasized as well that while pre-agricultural peoples certainly did consume saturated fat, it cannot compare with the levels consumed by modern Western populations. Bang and Dyerberg's data [1980] on Eskimo populations who ate a high-meat diet is particularly illustrative of this. Of the total dietary fats, saturated fats comprised 22.8% in Inuit people whereas saturated fats comprised 52.7% of the total dietary fats in a control population of Danes. To point to saturated fat consumption in pre-agricultural groups as license to eat freely of such fats ignores the ecological constraints that would have made modern levels of consumption highly unlikely for our paleolithic ancestors, and ignores as well the voluminous clinical data that shows their detrimental effects.

High levels of saturated fat consumption on a year-round basis only became possible when domesticated animals were bred and fed in a manner which allowed accumulation of depot fat on a year-round basis. Wild animals almost always show a seasonal variation in storage fat, and even the very fattest wild land mammals contain 60-75% less total fat than the average domesticated animal. Thus, until the advent of the "Agricultural Revolution" 10,000 years ago, it would have been extremely difficult, or perhaps impossible, to eat high levels of saturated fat on a daily basis throughout the year.

Limitation of the Keys equation in predicting expected serum cholesterol levels from fat and cholesterol in the diet

In our group over the last month or so, we have bandied about the idea of the ancestral macronutrient compositions (i.e., percent fat, protein, and carbohydrate) and how they influence health. Clearly, in the normal Western diet (approximately 45-50% carbohydrate, 35-40% fat, and 10-15% protein), if dietary saturated fats are reduced, then total and LDL cholesterol are also reduced. Keys [1965] has published an equation which has been used extensively to predict changes in serum cholesterol from dietary lipids and cholesterol. Others [Mensink 1992] more recently have confirmed Keys' equation.

However, in perhaps the most well-controlled, modern dietary study of Greenland Eskimos [Bang and Dyerberg 1980], it has been shown that ischemic heart disease is very uncommon in these people (3.5% vs. 45-50% mortality rate in Western countries). The dietary macronutrient content of these partially Westernized Eskimos was 38% carbohydrate, 39% fat, and 23% protein, whereas the values for the control group of Danish people were 47% carbohydrate, 42% fat, and 11% protein. Mean total cholesterol levels in the Eskimos (5.03 mmol/liter) were significantly lower than in the Danes (6.18 mmol/liter) whereas triglycerides (TG) (0.57 vs. 1.23 mmol/liter) and VLDL (0.43 vs. 1.29 mmol/liter) were much lower in the Eskimos, and HDL levels were significantly higher (4.00 vs. 3.34 mmol/liter).

Based upon the Keys et al. equation, the actual difference between the Eskimos' and Danes' total cholesterol levels should have been 0.67 mmol/liter, whereas in actuality it was 1.15 mmol/liter. This data suggests that the Keys equation may be invalid under circumstances wherein high quantities of animal products replace traditionally grain-dominated diets. Possible reasons for this discrepancy include the following characteristics of the Eskimos' diet:

• Higher protein levels in the face of lowered carbohydrate may induce different lipoprotein transport mechanisms [Wolfe 1995], and/or

• Differences in polyunsaturated fats between the two diets (high levels of n3 fats, and high levels of preformed long-chain fats of both n3 and n6 families).

Comment: To clarify the above, it appears that the likely reason the Keys equation fails to correctly predict cholesterol levels in situations such as the Eskimo study above is that it does not take into account the effects of carbohydrate on insulin secretion. Hyperinsulinemia now appears as if it may be one of the largest risk factors for CHD. Both high-protein and low-carbohydrate intakes, which were seen in the Eskimo study, promote inhibition of excess insulin.

Exactly. Ancestral, pre-agricultural diets were quite high in animal protein, and the carbohydrate that was consumed was generally of a low glycemic index. These populations also selectively consumed the fatty portions of the killed animal (brain, bone marrow, depot fat, perinephral fat, mesenteric fat, tongue, organs, etc.). However, available evidence from living hunter-gatherers show that these surrogates of our Stone-Age ancestors maintain low risk factors for CHD (blood lipid profiles, blood pressure, insulin sensitivity, body composition, etc.). All of this on a diet which contains an average 50-65% of its total calories derived from animal foods, which therefore necessarily entails lower carbohydrate consumption.

Clearly, the Keys equation breaks down when either the macronutrient content (high protein and low carbohydrate) or the fatty-acid composition of the diet (or both) varies beyond the range of conditions from which Keys originally derived his regression. Although there is much circumstantial evidence to indicate that the Keys equation is erroneous under these conditions, there is no empirical data that I am aware of which has specifically investigated or confirmed this concept.

Clarification of the role of saturated fats in promoting high cholesterol

Comment: Some who promote diets based on those of traditional peoples--who may at times have eaten higher levels of saturated fat--suggest that the modern (high) levels of CHD do not have anything to do with saturated fat from animal sources. Rather, they point to modern processing techniques as having introduced new food substances into the human diet with detrimental effects, particularly excess polyunsaturates, hydrogenated oils, and refined carbohydrates.

There is much evidence to support the second half of this sentiment, but the evidence does not agree with the first part.

• Hydrogenated oils (trans fatty acids), refined carbohdrates, and polyunsaturates. There is now substantial evidence that hydrogenated oils (trans fats) are atherogenic via their hypercholesterolemic effects [Willett et al. 1994]. And in terms of their cholesterol-raising properties they may be worse than saturated fats, because they cause a decrease in HDL cholesterol [Ascherio et al. 1997]. Refined carbohydrate (sucrose in particular) has been known for more than 30 years [Yudkin 1972] to be implicated in its CHD-promoting effects, probably through increases in VLDL (the precursor to LDL), triglycerides, total cholesterol, and perhaps decreases in HDL [Hollenbeck et al. 1989]. Recently it has been recognized that although dietary polyunsaturates may lower serum cholesterol levels, they may actually increase the risk for CHD by increasing the susceptibility of LDL to oxidation [Louheranta et al. 1996].

  So I am in agreement that hydrogenated fats, refined carbohydrates, and excessive polyunsaturated fats (primarily linoleic acid, 18:2n6) contribute to the development of CHD via hypercholesterolemic and LDL-oxidizing mechanisms.

• Saturated animal fats in overall dietary context. However, I cannot agree with the statement that saturated fats from animals in modern diets have nothing to do with CHD. It may be possible that the hypercholesterolemic effects of saturated fats (12:0, 14:0, 16:0) can be negated or somewhat ameliorated by extremely low levels of dietary carbohydrates (particularly in insulin-resistant subjects) or by high levels of dietary protein (>20% of total calories) via protein's VLDL-suppressing effects [Kalopissis et al. 1995].

  However, it is clear beyond a shadow of a doubt that dietary saturated fats (12:0, 14:0, and 16:0) elevate serum cholesterol levels within the context of the "average American diet." A recent meta-analysis of 224 published studies encompassing 8,143 subjects (many under metabolic ward conditions) has unequivocally demonstrated the hypercholesterolemic effect of dietary saturated fats [Howell et al. 1997]. The cellular basis for this observation stems from the regulation of low-density lipoproteins (LDLs). When the amount of cholesterol or saturated fat coming into the body is increased, there is an expansion of the sterol pools within liver cells, and to a lesser extent, peripheral cells, which causes a down-regulation of LDL receptors. As a consequence, LDL in plasma increases [Dietschy 1997].

  Some have argued that increases in total plasma cholesterol and LDL may not necessarily have a direct relationship to mortality from CHD [Stamler et al. 1986]. Clearly, there are a wide variety of independent risk factors for CHD including hypertension, homocysteine (increased by deficiencies primarily in folate, vitamin B-6, and secondarily in B-12), catecholamines, n6/n3 fatty-acid ratio, antioxidant status (vitamins E, C, beta-carotene, phytochemicals, etc.), dietary fiber, cigarette smoking, and ethanol (alcohol) consumption, which influence a variety of physiological systems involved with CHD. However, there is powerful evidence (n = 356,222) to indicate that the relationship between serum cholesterol levels and the risk of premature death from CHD is, nevertheless, continuous and graded [Stamler et al. 1986].

  Therefore, the recommendation by some that it is harmless to consume high levels of dietary saturated fats within the context of the "average American diet" appears to not only be erroneous, but probably deadly. Our hunter-gatherer ancestors consumed high levels of animal food (probably >55% of their total daily calories); however, the context under which this was done was much different than present-day conditions.

  As I have previously mentioned, the carbohydrate content of the diet was low (~<35% of total calories) and composed of plant foods with high soluble fiber and low starch content. The protein content of the diet would have exceeded 20% and may have been as high as 30-40%. The polyunsaturated fats consumed would have had a low n6/n3 ratio, and there would have been both ample levels of 20 and 22-carbon fats of both the n6 and n3 variety. Since marrow contains 70-75% monounsaturated fats and was a favored food, it is likely that although the fat content of the diet may have been as high as 40%, it was composed of not only a much more favorable n6/n3 polyunsaturated fat ratio, but higher levels of monounsaturated fats and non-atherogenic saturated fats such as stearic acid (18:0) as well.

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