Lipid hypothesis

With the emergence of cardiovascular disease as a major cause of death in the Western world in the middle of the 20th century, the lipid hypothesis received greater attention. In the 1940s, a University of Minnesota researcher, Ancel Keys, postulated that the apparent epidemic of heart attacks in middle-aged American men was related to their mode of life and possibly modifiable physical characteristics.[13] He first explored this idea in a group of Minnesota business and professional men that he recruited into a prospective study in 1947, the first of many cohort studies eventually mounted internationally. The first major report appeared in 1963 and the men were followed through until 1981.[14] After fifteen years follow-up, the study confirmed the results of larger studies that reported earlier on the predictive value for heart attack of several risk factors: blood pressure, blood cholesterol level, and cigarette smoking.

Keys presented his diet-lipid-heart disease hypothesis at a 1955 expert meeting of the World Health Organization in Geneva.[15] In response to criticism at the conference, Keys recruited collaborating researchers in seven countries to mount the first cross-cultural comparison, the years-long Seven Countries Study, which is still under observation today. This was to compare the heart attack risk in populations of men engaged in traditional occupations and being from cultures with different diets, especially in the proportion of fat calories of different composition.[16] There was also been criticism before the study began: Yerushalmy and Hilleboe pointed out that Keys had selected for the study the countries that would give him the results he wanted, while leaving out data from sixteen countries that would not; they also pointed out that Keys was studying a "tenuous association" rather than any possible proof of causation.[17] Keys then joined the nutrition committee of the American Heart Association (AHA), successfully promulgated his idea, and in 1961 the AHA became the first group anywhere in the world to advise cutting back on saturated fat (and dietary cholesterol) to prevent heart disease.[18] This historic recommendation was reported on the cover of Time Magazine in that same year.[19]

The Seven Countries Study was formally started in fall 1958 in Yugoslavia. In total, 12,763 males, 40–59 years of age, were enrolled in seven countries, in four regions of the world (United States, Northern Europe, Southern Europe, Japan). One cohort is in the United States, two cohorts in Finland, one in the Netherlands, three in Italy, five in Yugoslavia (two in Croatia, and three in Serbia), two in Greece, and two in Japan. The entry examinations were performed between 1958 and 1964 with an average participation rate of 90%, lowest in the US, with 75% and highest in one of the Japanese cohorts, with 100%.[20]

Keys' book Eat Well and Stay Well[21] popularized the idea that reducing the amount of saturated fat in the diet would reduce cholesterol levels and the risks of serious diseases due to atheroma.[22] Keys was followed during the rest of the 20th century by an accumulation of work that repeatedly demonstrated associations between cholesterol levels (and other modifiable risk factors including smoking and exercise) and risks of heart disease. These led to the acceptance of the lipid hypothesis as orthodoxy by much of the medical community.[3] By the end of the 1980s, there were widespread academic statements that the lipid hypothesis was proven beyond reasonable doubt,[23][24][25] or, as one article stated, "universally recognized as a law."[26][27][28][29][30]

The medical consensus supports the lipid hypothesis as evidence from separate meta-analyses, prospective epidemiologic studies and randomized clinical trials have demonstrated that elevated levels of LDL blood cholesterol are a significant risk factor for cardiovascular disease.[4] Too much LDL (called 'bad cholesterol') can lead to fatty deposits building up in the arteries which increases the risk of cardiovascular disease. A 2017 consensus statement from the European Atherosclerosis Society concluded that "consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD."[4] The consensus statement noted:

Most publications that question the causal effect of LDL on the development of ASCVD tend to cite evidence from individual studies or a small group of highly selected studies, often without a quantitative synthesis of the presented evidence. Therefore, to avoid this type of selection bias, we have based our conclusions on the totality of evidence from separate meta-analyses of genetic studies, prospective epidemiologic studies, Mendelian randomization studies, and randomized clinical trials. This evidence base includes over 200 studies involving over 2 million participants with over 20 million person-years of follow-up and more than 150 000 cardiovascular events. Together these studies provide remarkably consistent and unequivocal evidence that LDL causes ASCVD.[4]

A small number of "cholesterol skeptics", particularly those in The International Network of Cholesterol Skeptics (THINCS), take a contrary position to the accepted scientific consensus of the lipid hypothesis, claiming instead that heart disease is not caused by elevated LDL, and demonizing the cholesterol-lowering drugs statins.[31]

In 2016, Uffe Ravnskov, director of THINCS, was the lead author of a systematic review to examine how low-density lipoprotein cholesterol is associated with mortality in older adults. They concluded that "High LDL-C is inversely associated with mortality in most people over 60 years" and since "elderly people with high LDL-C live as long or longer than those with low LDL-C, our analysis provides reason to question the validity of the cholesterol hypothesis."[32] The review has been criticized for cherry picking data and confirmation bias. Nine of the authors are members of THINCS. The National Health Service noted that "the review searched only a single literature database, excluded studies only available in non-English language, and excluded studies where the title and abstract did not appear to contain information on the link between LDL and mortality in older adults."[33] Several medical experts responded to the review claiming it had a number of "serious weaknesses" and was contradicted by robust experimental data from clinical trials. Professor Jeremy Pearson Associate Medical Director of the British Heart Foundation commented that "there is nothing in the current paper to support the authors' suggestions that the studies they reviewed cast doubt on the idea that LDL cholesterol is a major cause of heart disease or that guidelines on LDL reduction in the elderly need re-evaluating."[34][35]

The "lipid hypothesis of osteoporosis" postulates that lipids involved in causing heart disease also contribute to causing osteoporosis. Osteoporosis is characterized by a decrease of bone marrow cells, or osteoblasts, and an increase of fat cells, or adipocytes. The formation of osteoblasts from pre-osteoblasts is reduced by oxidized lipids and in mice fed with a high fat diet. Observations from this model suggest that LDL oxidation products can cause osteoporosis through changing the developmental fate of bone cells leading to a reduced number of osteoblasts and increased numbers of fat cells.[36]

In plants and microbes, changes in the lipid composition of cell membranes have been linked to cold tolerance.[37] The enhanced resistance to cold treatment appears to be caused by an increased amount of fatty acid desaturases produced under cold stress transforming saturated into unsaturated fatty acids in the membrane. This effect can be reproduced artificially in genetically engineered plants.[38] The changes in membrane lipid composition lead to a higher membrane fluidity, thus keeping the membrane from "freezing" at low temperatures. This "lipid hypothesis of cold tolerance" is less well supported in animals. In fruit flies, cold acclimation does not coincide with a reduced amount of saturated fatty acids,[39] and recent genetic studies on a nematode indicate that the mechanisms involved in cold adaptation in animals may be different from those in plants and microbes.[40]