The lipid hypothesis is a medical theory postulating a link between blood cholesterol levels and occurrence of heart disease. A summary from 1976 described it as: "measures used to lower the plasma lipids in patients with hyperlipidemia will lead to reductions in new events of coronary heart disease". Or, more concisely, "decreasing blood cholesterol... significantly reduces coronary heart disease". An accumulation of evidence has led to the acceptance of the lipid hypothesis by most of the medical community.
Development
The German pathologistRudolf Virchow described lipid accumulation in arterial walls. In 1913, a study by Nikolai Anitschkow showed that rabbits fed on cholesterol developed lesions in their arteries similar to atherosclerosis, suggesting a role for cholesterol in atherogenesis. By 1951, it was accepted that, although the causes of atheroma were still unknown, fat deposition was a major feature of the disease process. "The so-called fatty flecks or streaks of arteries are the early lesions of atherosclerosis and... may develop into the more advanced lesions of the disease."
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. 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. 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. One cohort is in the United States, two cohorts in Finland, one in the Netherlands, three in Italy, five in Yugoslavia, 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%. Keys' book Eat Well and Stay Well 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. Keys was followed during the rest of the 20th century by an accumulation of work that repeatedly demonstrated associations between cholesterol levels and risks of heart disease. These led to the acceptance of the lipid hypothesis as orthodoxy by much of the medical community; By the end of the 1980s, there were widespread academic statements that the lipid hypothesis was proven beyond reasonable doubt, or, as one article stated, "universally recognized as a law." A 2017 consensus statement from the :de:European Atherosclerosis Society|European Atherosclerosis Society concluded that "consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD."
A small number of "cholesterol skeptics", particularly those in The International Network of Cholesterol Skeptics, take a contrary position to the accepted scientific consensus of the lipid hypothesis, claiming instead that heart disease is not caused by cholesterol, and demonizing the cholesterol-lowering drugs statins. A 1992 paper by Uffe Ravnskov looking a frequency of cholesterol-lowering trial citations, said that trials that were supportive of the lipid hypothesis were cited almost six times as often as those that were not, and although there was a similar number of trials unsupportive of the hypothesis, none of them were cited after 1970; some of the supportive reviews also exclude and ignore certain trials which were less favorable to the hypothesis. In particular, Keys' supplementary hypothesis that reducing saturated fat in the diet will reduce cardiovascular disease has been described by Ravnskov and by Gary Taubes as a "fallacy". A meta-analysis in 2014 finds that "current evidence does not clearly support cardiovascular guidelines that encourage high consumption of polyunsaturated fatty acids and low consumption of total saturated fats". This meta-analysis was called "seriously misleading" by Walter Willet, chair of the Department of Nutrition at Harvard, who explained that the paper contained major errors and omissions, most notably that the foods used to replace saturated fats were other unhealthy foods like refined sugars and starches. 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." 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." 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."
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.
Lipid hypothesis of cold tolerance
In plants and microbes, changes in the lipid composition of cell membranes have been linked to cold tolerance. 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. 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, 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.
