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. 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 men were followed through 1981 and the first major report appeared in 1963.[8] 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. Meanwhile, in the mid-1950s, with improved methods and design, Keys recruited collaborating researchers in seven countries to mount the first cross-cultural comparison of heart attack risk in populations of men engaged in traditional occupations in cultures contrasting in diet, especially in the proportion of fat calories of different composition, the Seven Countries Study still under observation today. Even before the study had begun, there had been criticism of its methods. 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.[9]

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 USA, with 75% and highest in one of the Japanese cohorts, with 100%.[10] Keys' book Eat Well and Stay Well[11] popularized the supplementary idea that reducing the amount of saturated fat in the diet would reduce cholesterol levels and the risks of serious diseases due to atheroma.[12] 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,[13][14][15] or, as one article stated, "universally recognized as a law."[16][17][18][19][20]

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."[21]

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.[32]

In plants and microbes, changes in the lipid composition of cell membranes have been linked to cold tolerance.[33] 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.[34] 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,[35] 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.[36]