Is saturated fat bad?

Published in Modern Dietary fat intakes in disease promotion. Nutr Health 2010, part 2, p 109-119 

Uffe Ravnskov, MD, PhD
Magle Stora Kyrkogata 9, S-22350 Lund, Sweden
Telephone and fax  +46 46145022
Email address: ravnskov@tele2.se

Abstract

To-day a reduction of the intake of saturated fat is one of the cornerstones in dietary prevention of obesity, diabetes and cardiovascular disease. However, several recent trials have documented that the main argument for this advice, its alleged influence on blood cholesterol, is questionable. More disturbing is that a large number of epidemiological, clinical, pathological and experimental studies have falsified the idea that a high intake is harmful to human health and that a reduction may be beneficial; indeed, several observations point to the opposite.

Background

For many years we have been taught that too much fat, in particular saturated fat in our diet may lead to overweight, diabetes and cardiovascular disease. According to a joint WHO/FAO Expert Consultation [1] “the relationship between dietary fats and CVD, especially coronary heart disease, has been extensively investigated, with strong and consistent associations emerging from a wide body of evidence”. This statement was followed by a reference to a consensus report from the Nutrition Committee of the American Heart Association [2]. The only evidence presented in that paper or in other official documents for an atherogenic effect of saturated fat is its effect on the blood lipids and a single cohort study claimed to have shown that intake of saturated fat is associated with an increased risk of coronary disease [3]. Most disturbing is that the numerous contradictory epidemiological, pathological and clinical observations as well as the unsupportive results from the dietary trials, the most important proof of causality, have been ignored by all guideline authors.

Any idea can be verified if one seeks for confirmation only, but a scientific hypothesis demands that it is able to present predictions that can be falsified. According to Karl Popper´s principle the assumption that a high intake of saturated fat may worsen human health is a true scientific hypothesis, because there are at least three major predictions that are open for falsification:

1. Obesity, diabetes, atherosclerosis and cardiovascular disease should be more common in populations with a high intake of saturated fat.

2. People with these maladies should have had a higher intake of saturated fat than healthy people of the same age and sex

3. A reduction of the intake of saturated fat should lower the risk.

These three logical assumptions have been falsified by many researchers, however. Consequently, objections against the vilification of saturated fat have been put forward [4-9], but they have made little impact on the official health policy. Since then even more contradictory findings have been published. This paper is an attempt to present a review of the full range of studies that in various ways have tested the mentioned predictions. As almost all of them contradict the current view and as some of them even point to a beneficial effect of saturated fat, the only possible conclusion of the accumulated evidence is that the hypothesis has been falsified effectively.

The influence of saturated fat on the blood lipids

The allegation that a high intake of saturated fat raises cholesterol is indirect evidence. Therefore, even if it were not true this finding cannot be used as a falsification of the hypothesis. However, it seems relevant to analyse this question as well because of its major role in the WHO guidelines. The idea was questioned by Reiser already in 1973. In a thorough review of 40 trials he pointed at several types of methodological and interpretational errors [10]. Instead of natural saturated fat many authors had used vegetable oils saturated by hydro- genation, and effects on cholesterol were attributed to saturated fat when it could be due to polyunsaturated fat as well. In spite of these flaws several authors maintain that saturated fat raises cholesterol,  whereas monounsaturated and in particular polyunsaturated fat lower it, and some saturated fatty acids my be neutral [11-15]. These conclusions have been based mainly on mathematical formulas using data from a large number of trials. But as almost all trial directors have made similar errors as those reviewed by Keys by changing  the intake of several fats at the same time without controlling for intake of trans fat it is obviously difficult to rule out the effect of each type of fat.

Even if saturated fat is hypercholesterolaemic the effect must be small. In a review of eight trials where the intake was reduced by 30-40 %  the net reduction of cholesterol was only 0-4 % [16], and other studies have shown no effect at all. In experiments for instance, where carbohydrates were substituted with saturated fat, not even intakes between 20 % and 50 % of calories influenced total or LDL-cholesterol (table 1) [17-26].

Table 1. Changes of blood lipids after a low-carbohydrate diet rich in saturated fat in
ten trials. In all trials the concentration of triglycerides went down significantly.
+ means that the intake of saturated fat was unlimited.
An argument for a hypercholesterolaemic effect is the increased levels of LDL receptors on mononuclear cells seen after a reduction of dietary saturated fat without changing the intake of unsaturated fat, but the authors did not control for trans fat either [27]. That other factors may override a possible hypercholesterolemic effect is obvious from studies of populations who live almost entirely on animal food, but have extremely low cholesterol [28-30]. In accordance, many cross-sectional studies of the dietary habits within a population have found no association between cholesterol and the intake of saturated fat [31-36].

In the abovementioned low-carbohydrate trials (table 1) a high intake of saturated fat had no adverse effects on other lipids either. On the contrary HDL-cholesterol remained unchanged or went up and triglycerides went down significantly (table 1) [18-27] whereas a reduction of the intake had the opposite effects [37-39]. As cardiovascular disease is stronger associated with small-size LDL than with other lipid fractions it is also contradictory that high intakes of saturated fat are followed by an increase of LDL size [37,40,41].

Effects of saturated fat on the blood lipids is surrogate outcome, however. The crucial question is whether a high intake of saturated fat is deleterious to health and whether a reduction of the intake is beneficial.

Ecological studies

There is little evidence from epidemiological studies that high intakes of saturated fat leads to cardiovascular disease. Ancel Keys introduced the idea that dietary fat plays a pathogenic role in heart disease. His main argument was a strong, curvilinear correlation between heart mortality and the total amount of fat available for consumption in six countries [42]. However, Keys had selected his data. At that time figures for fat consumption and heart mortality were obtainable from 22 countries and if all of them were included the association became trivial [43], and an analysis based on the totality of more recent data that included 35 countries found an inverse association [4].

These studies concerned total fat, but similar data for saturated fat are contradictory as well, as appears best from dynamic population studies. Several authors of such studies have used concurrent trends of saturated fat consumption and coronary mortality in a single country as an argument for causality. Parallel changes may occur by chance, however, clearly demonstrated by a review of 103 time periods in 35 countries. Here, consumption of saturated fat increased in 63 periods; in 33 of these periods heart mortality increased as well, but in ten periods it was unchanged and in 23 it went down [4].

Cross-sectional studies

In a review of cross-sectional studies of the association between intake of saturated fat and coronary heart disease (CHD) an association was found in a few only, whereas more than 30 studies were partly or totally contradictive [4,44]. A few of the most contradictory observations are worth mentioning.

In seven studies of American Indians coronary mortality was only 10-50 % of the mortality of white Americans and degree of atherosclerosis was much smaller although their intake of saturated fat was similar or higher [4].

A study of Japanese emigrants in the US apparently was in support and is often used as an argument because after migration their low cholesterol rose to American levels, as did their risk of dying from CHD. However, the determining factor was not the diet or their cholesterol but their way of living. Those who maintained their cultural traditions were protected against CHD although their cholesterol went up. Even more striking was that immigrants who became accustomed to the American way of life, but preferred the lean Japanese food had CHD twice as often as those who maintained Japanese traditions, but preferred high-fat American food [45].

In a five-year follow-up study of more than 1 million male employees of the Indian railways Malhotra found that the lowest and highest rates of coronary mortality were seen in Punjab and Madras, 20 and 135 per 100,000 employees, respectively, and the mean age at death was 12 years lower in Madras than in Punjab. But in Punjab people ate about 17 times more fat than in Madras, the main part of which was of animal origin. In addition more people smoked in that area [46].

In a study considered as the strongest argument for the diet-heart idea Keys selected 16 cohorts in seven countries and found an association between intake of saturated fat and the prevalence and 5-year incidence of coronary mortality [47]. But within each country there was little or no association at all although all risk factors including the intake of saturated fat were similar. Coronary mortality for instance was more than twice as high in Crevalcore, Italy than in Montegiorgio, five times higher in Karelia than in West Finland and 16-17 times higher on Corfu than on Crete. In addition, no association was seen between intake of saturated fat and major ECG abnormalities at entry. The latter finding has more importance considering that the ECGs were analysed by specialists in the American centre, whereas the cause of death was determined by local doctors with varying competence.

Cohort and case-control studies of saturated fat intake

The diet of coronary patients and healthy individuals has been compared in numerous cohort and case-control studies. In a previous review of 28 cohorts in 21 studies patients with CHD had eaten significantly more saturated fat than the controls in three cohorts, but the differences were trivial, in one cohort they had eaten significantly less and in the other 24 cohorts no differences were seen [4]. No difference was seen either in two recent, large cohort studies [48-49], or in the study referred to by the WHO guideline authors; in the latter the statistical significance disappeared after controlling for other dietary factors [3].

No difference in fat intake was seen either in three case control studies between patients with CHD and control individuals of the same age and sex [50-52]. It can be argued that case control studies may be confounded by changes in the diet after the diagnosis of heart disease, but the mentioned studies were performed between 1958 and 1968 before dietary advices had become standard treatment.

Even more contradictory are the findings in stroke patients. In ten prospective cohort studies of healthy people the authors compared the intake of saturated fat in those who had stroke at follow-up with the intake of the others [53-62] . With one exception [60] all studies found that stroke patients had eaten less saturated fat than had the non-stroke individuals; in six of the studies  the difference was statistically significant (table 2).

Table 2. Association between intake of saturated fat and stroke in ten cohort studies.
* p<0.05; ** P<0.01

A relevant objection against such studies is that dietary information is inaccurate. A more reliable way to study previous intakes with disease is analyses of fat tissue, because intake of saturated fat during the last weeks or months is reflected by the levels of individual fatty acids in the fat tissue. The strongest associations are found between intake and concentrations of the short chain acids 12:0-15:0 [63-67], and of the total numbers [68-71], but weakly or not at all of the longer ones, probably because a high intake of simple carbohydrates stimulates endogenous synthesis of the long chain saturated fatty acids [72].

In three case-control studies of patients with myocardial infarction and healthy controlindividuals no difference was found as regards the content of the short-chain saturated fatty acids; in two studies it was even significantly lower in the patients (Table 3) [73-77]. These studies concerned only patients with first myocardial infarction [74-77] or patients who were not on a diet [73], and a diet bias is therefore unlikely.

Table 3.Five case-control studies of the content of short-chain saturated fatty acids
in the fat tissue of patients with myocardial infarction and of healthy control
individuals.
*p<o.o5; **p<0.01

Saturated fat intake and atherosclerosis

If high intakes of saturated fat should lead to atherosclerosis, people with high intakes should be  more atherosclerotic than people with low intakes. No such association has been found in any study. In the International Atherosclerosis Project, fifteen populations were ranked by raised atherosclerosis and by selected diet components. Degree of atherosclerosis was associated  with the total fat intake, but not with the intake of saturated fat [78]. In three cohort studies of healthy individuals followed for several years, post-mortems of those who had died at follow-up found no association either between intake of saturated fat and degree of atherosclerosis [79-81]. No association was found either between the content of 14:0 and 15:0 saturated fatty acids in the fat tissue and degree of atherosclerosis, determined either by autopsy [82] or by coronary angiography [83].

Angiographic follow-up studies have given disparate results. In a trial including 50 men with CHD, where a low-fat diet was compared with usual care, progress of the angiographic changes over 39 months was associated with intakes of palmitic and stearic acids [84]. However, the group that ate the low-fat diet was also instructed to increase their intake of fish, fruit and vegetables, and intake of such food have been found inversely associated with the risk of CHD in almost all studies.

In the MARGARIN study 81 hypercholesterolaemic individuals were followed for two years after having received dietary advice [85]. At follow-up associations between the changes of intima-media thickness of the coronary and femoral arteries, measured by ultrasound, and intake of saturated fat were not significant in multivariate regression analyses. When the patients were grouped into quintiles of change of saturated fat intake, a weak association was seen with the changes of the femoral, but not with the changes of the coronary arteries. However, a similar bias was introduced in that study also, because vascular changes were inversely associated with intake of fruit. As the effect of a reduced intake of saturated fat is said to be due to a lowering of LDL cholesterol it is also contradictory that LDL cholesterol was lowest in those whose intake of saturated fat had increased during the study period. In contrast, a highly significant inverse association was found between intake of saturated fat and progress of angiographic lesions in a 3-year follow-up study of 235 postmenopausal women with CHD [86].

Saturated fat and type 2 diabetes

Epidemiological studies have found a high intake of saturated fat to be associated with higher fasting blood glucose and a greater  risk of developing type 2 diabetes, and several such studies are cited in the WHO guidelines. The associations were weak, however and in the largest study that included more than 50,000 individuals the association disappeared after correction for other factors. The authors concluded that an incomplete control of physical activity and other dietary factors might have influenced the results in the previous studies [87].  That a high intake of saturated fat should predispose for type 2 diabetes is contradicted by experiments with diets poor in carbohydrates and rich in saturated fat. No worsening of the diabetic condition were seen in these experiments; on the contrary most of them showed an improvement of insulin sensitivity, a lowering of HbA1C and some of the patients were able to stop or lower their antidiabetic treatment [18,20,21,24,25,27,88].

Saturated fat and body weight

Fat has more calories per weight unit than have carbohydrates and protein. This is one of the main arguments for the advise to obese patients to exchange dietary fat with carbohydrates, although there is no evidence that fat per ingested calorie is more fattening than carbohydrates. The increase of mean body weight seen in many Western countries since the introduction of the  low-fat diet rather points at the opposite. Meta-analyses of controlled trials of calorie restriction by fat reduction have found that this regime may lead to weight loss, but the effect is trivial and is not sustainable. Willett and Leibel have pointed at serious errors in most of these studies; many of them were not randomised, there were multiple reports from the same trial, fat reduction was combined with increased physical activity and other weight-reducing measures and long-term studies were excluded. Their most serious objection is that the fat reduction and control groups did not receive a comparable intensity of dietary instruction and motivation [89]. A strong argument against the idea that a high intake of animal fat is more fattening than a low-fat diet is that in all trials mentioned in table 1 a greater weight loss was seen in those who were instructed to follow a high-fat diet than in those on a low-fat diet.

Dairy products

In many populations a major contribution of saturated fat comes from dairy products and all authoritative guidelines recommend a restriction of such food. However, in a meta-analysis of ten cohort studies including more than 400,000 individuals Elwood et al. found that compared with low-consumers the risks of myocardial infarction, ischaemic stroke and all cardiovascular events in high-consumers were 0.87 (0.74-1.03), 0.83 (0.77-0.90) and 0.84 (0.78-0.90) respectively [90]. In a thorough review of the associations between dairy products and cardiovascular disease Tolstrup found no strong evidence in support either [91]. Besides, in a study of adolescents the low-chain fatty acids 4:0-10:0, 12:0 and 14:0, that closely reflected the intake of milk [65] were inversely associated with serum cholesterol [92]. The studies of fat tissue fatty acids mentioned above are contradictive as well.

The dietary trials

The most important argument for causality is improvement or disappearance of the disease after decrease or discontinuation of the exposure to the suspected causal factor. To-day relevant data have been published from nine randomised, controlled trials where the only intervention was a change of dietary fat. Two meta-analyses of these trials found no significant effect, neither on cardiovascular or total mortality [4,93,94], and as mentioned above, most trials comparing high-carbohydrate-low-saturated fat diets with low-carbohydrate-high-saturated fat have found a better outcome as regards body weight an metabolic control in the latter ones.

Conclusions

The idea that too much saturated fat in the diet is harmful to human health has no support from ecological, dynamic population, or case-control studies of the association between dietary saturated fat, or tissue saturated fatty acids, and cardiovascular disease, nor from meta-analyses of randomised, controlled, unifactorial dietary trials. Even if the author of this review has studied the scientific literature on this issue meticulously for eighteen years, supportive studies may have been overlooked. However, a scientific hypothesis must be in accord with all observations; a few supportive studies cannot outweigh more than hundred studies that have falsified the hypothesis.…

References

1. Diet, nutrition and the prevention of chronic diseases. Report of a joint WHO/FAO expert consultation. WHO Technical Report Series 916, Geneva 2003.

2. Kris-Etherton P et al.:Summary of the scientific conference on dietary fatty acids and cardiovascular health:
conference summary from the nutrition committee of the American Heart Association. Circulation 2001, 103:034-1039.

3. Hu FB, Stampfer MJ, Manson JE, Rimm E, Colditz GA, Rosner BA, Hennekens CH, Willett WC: Dietary fat intake and the risk of coronary heart disease in women. N Engl J Med 1997, 337:1491-1499.

4. Ravnskov U: The questionable role of saturated and polyunsaturated fatty acids in cardiovascular disease. J Clin Epidemiol 1998, 51:443-460.

5. Olson R: Is it wise to restrict fat in the diets of children? J Am Diet Assoc 2000, 100:28-32.

6. Taubes G: The soft science of dietary fat. Science 2001, 291:2535-2541.

7. Weinberg SL: The diet-heart hypothesis: A critique. J Amer Coll Cardiol 2004, 43:731-733.

8. German JB, Dillard CJ: Saturated fats: what dietary intake? Am J Clin Nutr 2004, 80:550-559

9. Okuyama H (ed). Prevention of coronary heart disease. From the cholesterol hypothesis to ω6/ω3 balance. World Review of Nutrition and Dietetics, vol 96, New York, Karger; 2007.

10.  Reiser R: Saturated fat in the diet and serum cholesterol concentration: a critical examination of the literature. Am J Clin Nutr 1973, 26:524-555.

11.  Mensink RP, Katan MB: Effect of dietary fatty acids on serum lipids and lipoproteins. A meta-analysis of 27 trials. Arterioscler Thromb Vasc Dis 1992, 12:911-919.

12.  Hegsted DM, Ausman LM, Johnson JA, Dallal GE: Dietary fat and serum lipids: an evaluation of the experimental data. Am J Clin Nutr 1993, 57:875-883.

13.  Woodside JV, Kromhout D: Fatty acids and CHD. Proc Nutr Soc 2005, 64:554-564.

14.  Kuller LH: Nutrition, lipids, and cardiovascular disease. Nutr Rev 2006, 64:S15-26.

15.  Lapointe A, Balk EM, Lichtenstein AH: Gender differences in plasma lipid response to dietary fat. Nutr Rev 2006, 64:234-249

16.  Ramsay LE, Yeo WW, Jackson PR: Dietary reduction of serum cholesterol concentration: time to think again. BMJ 1991, 303:953-957.

17.  Noakes M, Foster PR, Keogh JB, James AP, Mamo JC, Clifton PM: Comparison of isocaloric very low carbohydrate/high saturated fat and high carbohydrate/low saturated fat diets on body composition and cardiovascular risk. Nutr Metab  2006, 3:7.

18.  Meckling KA, O’Sullivan C, Saari D: Comparison of a low-fat diet to a lowcarbohydrate diet on weight loss, body composition, and risk factors for diabetes and cardiovascular disease in free-living, overweight men and women. J Clin Endocrinol Metab 2004, 89:2717-2723.

19.  Sondike SB, Copperman N, Jacobson MS: Effects of a low-carbohydrate diet on weight loss and cardiovascular risk factor in overweight adolescents. J Pediatr 2003, 142:253-58.

20.  Sharman MJ, Gomez AL, Kraemer WJ, Volek JS: Very low-carbohydrate and low-fat diets affect fasting lipids and postprandial lipemia differently in overweight men. J Nutr 2004, 134:880-5.

21.  Hays JH, DiSabatino A, Gorman RT, Vincent S, Stillabower ME: Effect of a high saturated fat and no-starch diet on serum lipid subfractions in patients with documented atherosclerotic cardiovascular disease. Mayo Clin Proc 2003, 78:1331-1336.

22.  Westman EC, Yancy WS, Edman JS, Tomlin KF, Perkins CE: Effect of 6-month adherence to a very low carbohydrate diet program. Am J Med 2002, 113:30-36.

23.  Foster GD, Wyatt HR, Hill JO, McGuckin BG, Brill C, Mohammed BS: A randomized trial of a low-carbohydrate diet for obesity. N Engl J Med 2003, 348:2082-2090.

24.  Yancy WS Jr, Foy M, Chalecki AM, Vernon MC, Westman EC: A lowcarbohydrate, ketogenic diet to treat type 2 diabetes. Nutr Metab 2005, 2:34.

25.  Seshadri P, Iqbal N, Stern L, Williams M, Chicano KL, Daily DA, McGrory J, Gracely EJ, Rader DJ, Samaha FF: A randomized study comparing the effects of a low-carbohydrate diet and a conventional diet on lipoprotein subfractions and C-reactive protein levels in patients with severe obesity. Am J Med 2004, 117:398-405.

26.  Brehm BJ, Seeley RJ, Daniels SR, D’Alessio DA: A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab 2003, 88:1617-1623.

27.  Mustad VA, Etherton TD, Cooper AD, Mastro AM, Pearson TA, Jonnalagadda SS, Kris-Etherton PM: Reducing saturated fat intake is associated with increased levels of LDL receptors on mononuclear cells in healthy men and women. J Lipid Res 1997, 38:459-468.

28.  Shaper AG, Jones KW: Serum-cholesterol in camelherding nomads. Lancet 1962, 2:1305-7.

29.  Shaper AG. Cardiovascular studies in the Samburu tribe of Northern Kenya. Am Heart J 1962, 63:437-442.

30.  Mann GV, Shaffer RD, Anderson RS, Sandstead HH: Cardiovascular disease in the Masai. J Atheroscler Res 1964, 4:289-312.

31.  Morris JN, Marr JW, Heady JA, Mills GL, Pilkington TRE: Diet and plasma cholesterol in 99 bank men. BMJ 1963, 1:571-576.

32.  Kahn HA, Medalie JH, Neufeld HN, Riss E, Balogh M, Groen JJ: Serum cholesterol: its distribution and association with dietary and other variables in a survey of 10,000 men. Isr J Med Sci 1969, 5:1117-1127.

33.  Nichols AB, Ravenscroft C, Lamphiear DE, Ostrander LD Jr: Daily nutritional intake and serum lipid levels. The Tecumseh study. Am J Clin Nutr 1976, 29:1384-1392.

34.  Weidman WH, Elveback LR, Nelson RA, Hodgson PA, Ellefson RD. Nutrient intake and serum cholesterol level in normal children 6 to 16 years of age. Pediatrics 1978, 61:354-359.

35.  Frank GC, Berenson GS, Webber LS: Dietary studies and the relationship of diet to cardiovascular disease risk factor variables in 10-year-old children–The Bogalusa Heart Study.  Am J Clin Nutr 1978, 31:328-340.

36.  Wiltshire EJ, Gent R, Hirte C, Pena A, Thomas DW, Couper JJ: Dietary fats do not contribute to hyperlipidemia in children and adolescents with type 1 diabetes. Diabetes Care 2003, 26:1356-1361.

37.  Krauss RM, Blanche PJ, Rawlings RS, Fernstrom HS, Williams PT: Separate effects of reduced carbohydrate intake and weight loss on atherogenic dyslipidemia. Am J Clin Nutr 2006, 83:1025-31

38.  Volek JS, Sharman MJ, Forsythe CE: Modification of lipoproteins by very lowcarbohydrate diets. J Nutr 2005, 135:1339-1342.

39.  Velez-Carrasco W, Lichtenstein AH, Welty FK et al: Dietary restriction of saturated fat and cholesterol decreases HDL ApoA-I secretion. Arterioscler Thromb Vasc Dis 1999, 19:918-924.

40.  Wood RJ: Effect of dietary carbohydrate restriction with and without weight loss on atherogenic dyslipidemia. Nutr Rev 2006, 64:539-545.

41.  Westman EC, Yancy WS Jr, Olsen MK, Dudley T, Guyton JR: Effect of a lowcarbohydrate, ketogenic diet program compared to a low-fat diet on fasting lipoprotein subclasses. Int J Cardiol 2006, 110:212-216.

42.  Keys A: Atherosclerosis: A problem in newer public health. J Mount Sinai Hosp 1953, 20:118-139.

43.  Yerushalmy J, Hilleboe HE: Fat in the diet and mortality from heart disease. A methodological note. N Y State J Med 1957, 57:2343-2354.

44.  Ravnskov U. Hypothesis-out-of-date. The diet-heart idea. J Clin Epidemiol 2002, 55:1057-1063.

45.  Marmot MG, Syme SL: Acculturation and coronary heart disease in Japanese-Americans. Am J Epidemiol 1976, 104:225-247.

46.  Malhotra SL: Epidemiology of ischaemic heart disease in India with special reference to causation. Br Heart J 1967, 29:895-905.

47.  Keys  A: Coronary heart disease in seven countries. Circulation 1970, 41(suppl 1):1-211.

48.  Leosdottir M, Nilsson PM, Nilsson JA, Månsson H, Berglund G: Dietary fat intake and early mortality patterns–data from The Malmö Diet and Cancer Study. J Intern Med 2005, 258: 153-165.

49.  Halton TL, Willett WC, Liu S, Manson JE, Albert CM, Rexrode K, Hu FB: Low-carbohydrate-diet score and the risk of coronary heart disease in women. N Engl J Med 2006, 355:1991-2002.

50.  Zukel WJ, Lewis RH, Enterline PE, Painter RC, Ralston LS, Fawcett RM, Meredith AP, Peterson B: A short-term community study of the epidemiology of coronary heart disease. A preliminary report on the North Dakota study. Am J Public Health 1959, 49:1630-1639.

51.  Finegan A, Hickey N, Maurer B, Mulcahy R: Diet and coronary heart disease: dietary analysis on 100 male patients. Am J Clin Nutr 1968, 21:143-148.

52.  Bassett DR, Abel M, Moellering RC Jr, Rosenblatt G, Stokes J 3rd: Coronary heart disease in Hawaii: dietary intake, depot fat, “stress”, smoking, and energy balance in Hawaiian and Japanese men. Am J Clin Nutr 1969, 22:1483-1503.

53.  Stemmermann GN, Hayashi T, Resch JA, Chung CS, Reed DM, Rhoads GG: Risk factors related to ischemic and hemorrhagic cerebrovascular disease at autopsy: the Honolulu Heart Study. Stroke 1984, 15:23-28.

54.  Takeya Y, Popper JS, Shimizu Y, Kato H, Rhoads GG, Kagan A: Epidemiologic studies of coronary heart disease and stroke in Japanese men living in Japan, Hawaii and California: incidence of stroke in Japan and Hawaii. Stroke 1984, 15:15-23.

55.  McGee D, Reed D, Stemmerman G, Rhoads G, Yano K, Feinleib M: The relationship of dietary fat and cholesterol to mortality in 10 years: the Honolulu Heart Program. Int J Epidemiol 1985: 14:97-105.

56.  Gillman MW, Cupples LA, Millen BE, Ellison RC, Wolf PA: Inverse association of dietary fat with development of ischemic stroke in men. JAMA 1997, 278:2145-2150.

57.  Ross RK, Yuan JM, Henderson BE, Park J, Gao YT, Yu MC: Prospective evaluation of dietary and other predictors of fatal stroke in Shanghai, China. Circulation 1997, 96:50-55. Seino F, Date C, Nakayama T, Yoshiike N, Yokoyama T, Yamaguchi M, Tanaka H: Dietary lipids and incidence of cerebral infarction in a Japanese rural community. J Nutr Sci Vitaminol 1997, 43:83-99.

58.  Iso H, Stampfer MJ, Manson JE, Rexrode K, Hu F, Hennekens CH, Colditz GA, Speizer FE, Willett WC: Prospective study of fat and protein intake and risk of intraparenchymal hemorrhage in women. Circulation 2001, 103:856-863.

59.  He K, Merchant A, Rimm EB, Rosner BA, Stampfer MJ, Willett WC, Ascherio A: Dietary fat intake and risk of stroke in male US healthcare professionals: 14 year prospective cohort study. BMJ 2003, 327:777-782.

60.  Iso H, Sato S, Kitamura A, Naito Y, Shimamoto T, Komachi Y: Fat and protein intakes and risk of intraparenchymal hemorrhage among middle-aged Japanese. Am J Epidemiol 2003, 157:32-39.

61.  Sauvaget C, Nagano J, Hayashi M, Yamada M: Animal protein, animal fat, and cholesterol intakes and risk of cerebral infarction mortality in the adult health study. Stroke 2004, 35:1531-1537.

62.  Thomson M, Fulton M, Wood DA, Brown S, Elton RA, Birtwhistle A, Oliver MF: A comparison of the nutrient intake of some Scotsmen with dietary recommendations. Hum Nutr Appl Nutr 1985, 39:443-455.

63.  Smedman AE, Gustafsson IB, Berglund LG, Vessby BO: Pentadecanoic acid in serum as a marker for intake of milk fat: relations between intake of milk fat and metabolic risk factors. Am J Clin Nutr 1999, 69: 22-9.

64.  Wolk A, Furuheim M, Vessby B: Fatty acid composition of adipose tissue and serum lipids are valid biological markers of dairy fat intake in men. J Nutr 2001, 131:828-833.

65.  Rosell M, Johansson G, Berglund L, Vessby B, de Faire U, Hellenius ML: Associations between the intake of dairy fat and calcium and abdominal obesity. Int J Obes Relat Metab Disord 2004, 28:1427-1434.

66.  Brevik A, Veierod MB, Drevon CA, Andersen LF: Evaluation of the odd fatty acids 15:0 and 17:0 in serum and adipose tissue as markers of intake of milk and dairy fat. Eur J Clin Nutr 2005, 59:1417-1422.

67.  Field CJ, Angel A, Clandinin MT: Relationship of diet to the fatty acid composition of human adipose tissue structural and stored lipids. Am J Clin Nutr 1985, 42:1206-1220.

68.  Schäfer L, Overvad K: Subcutaneous adipose-tissue fatty acids and vitamin E in humans: relation to diet and sampling site. Am J Clin Nutr 1990, 52:486-490.

69.  Tjønneland A, Overvad K, Thorling E, Ewertz M: Adipose tissue fatty acids as biomarkers of dietary exposure in Danish men and women. Am J Clin Nutr 1993, 57:629-633.

70.  Knutsen SF, Fraser GE, Beeson WL, Lindsted KD, Shavlik DJ: Comparison of adipose tissue fatty acids with dietary fatty acids as measured by 24-hour recall and food frequency questionnaire in Black and White Adventists: the Adventist Health Study. Ann Epidemiol 2003, 13:119-127.

71.  Hudgins LC, Hellerstein MK, Seidman CE, Neese RA, Tremaroli JD, Hirsch J: Relationship between carbohydrate-induced hypertriglyceridemia and fatty acid synthesis in lean and obese subjects. J Lipid Res 2000, 41:595-604.

72.  Kirkeby K, Ingvaldsen P, Bjerkedal I: Fatty acid composition of serum lipids in men with myocardial infarction. Acta Med Scand 1972, 192:513-519.

73.  Wood DA, Butler S, Riemersma RA, Thomson M, Oliver MF, Fulton M, Birtwhistle A, Elton R: Adipose tissue and platelet fatty acids and coronary heart disease in Scottish men. Lancet 1984, 2:117-121.

74.  Kark JD, Kaufmann NA, Binka F, Goldberger N, Berry EM: Adipose tissue n-6 fatty acids and acute myocardial infarction in a population consuming a diet high in polyunsaturated fatty acids. Am J Clin Nutr 2003, 77:796-802.

75.  Clifton PM, Keogh JB, Noakes M: Trans fatty acids in adipose tissue and the food supply are associated with myocardial infarction. J Nutr 2004, 134:874-879.

76.  Pedersen JI, Ringstad J, Almendingen K, Haugen TS, Stensvold I, Thelle DS: Adipose tissue fatty acids and risk of myocardial infarction–a case-control study. Eur J Clin Nutr 2000, 54:618-625.

77.  Scrimshaw NS, Guzmán MA: Diet and atherosclerosis. Lab Invest 1968, 18:623-628.

78.  Moore MC, Guzman MA, Schilling PE, Strong JP: Dietary-atherosclerosis study on deceased persons. Relation of selected dietary components to raised coronary lesions. J Amer Diet Assoc 1976, 68:216-223.

79.  Reed DM, MacLean CJ, Hayashi T: Predictors of atherosclerosis in the Honolulu Heart Program. I. Biologic, dietary, and lifestyle characteristics. Am J Epidemiol 1987, 126:214-225.

80.  Reed DM, Resch JA, Hayashi T, MacLean C, Yano K: A prospective study of cerebral artery atherosclerosis. Stroke 1988, 19:820-825.

81.  Scott RF, Daoud AS, Gittelsohn A, Opalka E, Florentin R, Goodale F: Lack of correlation between fatty acid patterns in adipose tissue and amount of coronary arteriosclerosis. Am J Clin Nutr 1962, 10:250-256.

82.  Lang PD, Degott M, Heuck CC, Opherk D, Vollmar J: Fatty acid composition of adipose tissue, blood, lipids, and glucose tolerance in patients with different degrees of angiographically documented coronary arteriosclerosis. Res Exp Med 1982, 180:161-168.

83.  Watts GF, Jackson P, Burke V, Lewis B: Dietary fatty acids and progression of coronary artery disease in men. Am J Clin Nutr 1996, 64:202-209.

84.  Bemelmans WJ, Lefrandt JD, Feskens EJ, Broer J, Tervaert JW, May JF, Smit AJ: Effect of an increased intake of alpha-linolenic acid and group nutritional education on cardiovascular risk factors: the Mediterranean Alpha-linolenic Enriched Groningen Dietary Intervention (MARGARIN) study. Am J Clin Nutr 2002, 75:221-2227

85.  Mozaffarian D, Rimm EB, Herrington DM: Dietary fats, carbohydrate, and progression of coronary atherosclerosis in postmenopausal women. Am J Clin Nutr 2004, 80:1175-184.

86.  van Dam RM, Willett WC, Rimm EB, Stampfer MJ, Hu FB: Dietary fat and meat intake in relation to risk of type 2 diabetes in men. Diabetes Care 2002, 25:417-424.

87.  Boden G, Sargrad K, Homko C, Mozzoli M, Stein P: Effect of a low-carbohydrate diet on appetite, blood glucose levels, and insulin resistance in obese patients with type 2 diabetes. Ann Intern Med  2005, 142:403-411.

88.  Willett WC, Leibel RL: Dietary fat is not a major determinant of body fat. Am J Med 2002, 113:47S-59S.

89.  Elwood PC, Pickering JE, Fehily AM, Hughes J, Ness AR: Milk drinking, ischaemic heart disease and ischaemic stroke. II. Evidence from cohort studies. Eur J Clin Nutr 2004, 58:718-724.

90.  Tolstrup T: Dairy products and cardiovascular disease. Curr Opin Lipidol 2006, 17:1-10.

91.  Samuelson G, Bratteby LE, Mohsen R, Vessby B: Dietary fat intake in healthy adolescents: inverse relationships between the estimated intake of saturated fatty acids and serum cholesterol. Br J Nutr 2001, 85:333-341.

92.  Hooper L, Summerbell CD, Higgins JP, Thompson RL, Capps NE, Smith GD, Riemersma RA, Ebrahim S: Dietary fat intake and prevention of cardiovascular disease: systematic review. BMJ 2001, 322:757-763.

93. Ravnskov U: Diet-Heart disease hypothesis is wishful thinking. BMJ 2002, 324:238.