Lipid hypothesis

The lipid hypothesis was one of two hypotheses developed in the 1850s to explain the pathogenesis of atherosclerosis. It was proposed by the German pathologist Rudolph Virchow in 1856 and suggested that blood lipid accumulation in arterial walls causes atherosclerosis.^[1] Since 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. An accumulation of evidence has led to the acceptance of the lipid hypothesis as scientific fact by the medical community;^[2] however, a small but vocal minority contend that it has not yet been properly validated, and that vascular inflammatory mechanisms prevail independent of blood cholesterol levels.

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The lipid hypothesis of atherogenesis

Early studies and origin of the lipid hypothesis

In 1913, a study by Nikolai Anitschkow showed that feeding rabbits cholesterol could induce symptoms similar to atherosclerosis, suggesting a role for cholesterol in atherogenesis.^[3][4] In 1951, Duff and McMillian formulated the lipid hypothesis in its modern form in a review which appeared in the American Journal of Medicine.^[5] One of the most well known early modern proponents that saturated fats and cholesterol in the blood are the cause of heart disease was Ancel Keys, whose first paper on the topic was published in 1953^[6], and whose book Eat Well and Stay Well^[7] helped the issue gain popular awareness.^[8]

Scientific consensus

Since the middle of the 20th century, the lipid hypothesis proposing that saturated fats and cholesterol in the blood are a major factor in cardiovascular disease has been the focus of research seeking to prove or disprove its validity. The interpretation of this research has resulted in the general acceptance of the lipid hypothesis as scientific fact by the end of the century.^[2] While it has attracted controversy, the scientific consensus was early on in its favor. A survey conducted in 1978 found that a large majority of researchers and practitioners were supportive of the validity of the lipid hypothesis.^[9] In this survey, 211 prominent researchers in the field were questioned about the association of the plasma cholesterol biomarker and the link of disease to diet. 90% responded with the following answers:

The National Institute of Health held a consensus development conference reviewing the scientific evidence in 1984, during which a panel of 14 experts unanimously voted "yes" on the questions of whether blood cholesterol was causal and whether reducing it would help to prevent heart disease.^[10] The panel concluded:

It has been established beyond a reasonable doubt that lowering definitely elevated blood cholesterol levels (specifically, blood levels of low-density lipoprotein (LDL) cholesterol) will reduce the risk of heart attacks caused by coronary heart disease...^[11]

As of the end of the 1980s, the evidence accumulated through studies resulted in general acceptance of the lipid hypothesis and the rejection of the "cholesterol controversy",^[12][13] and by 2002, the lipid hypothesis was accepted by the scientific community as proven,^[14] or, as one article stated, "universally recognized as a law."^[15] A minority of the medical community still argue that the lipid hypothesis has not yet been scientifically validated as a cause of heart disease.^[16][17]

Nowadays, the term "lipid hypothesis" is commonly used by the opponents of the scientific consensus concerning the role of cholesterol in atherosclerosis and cardiovascular disease, such as members of The International Network of Cholesterol Skeptics founded in 2003 by critic Uffe Ravnskov.

Controversy

The cholesterol controversy of atherogenesis

During the 70s and 80s, some researchers and practitioners considered the lipid hypothesis as unverified due to the lack of proof at that time that lowering blood cholesterol levels resulted in decreased risk for atherosclerosis.^[18] Some skeptics were questioning its validity by arguing that the studies supporting it were flawed.^[19][20] This discussion is also referred to as the "cholesterol controversy." Predictions were made at the time that further research during the 1980s and 1990s would help settle this controversy.^[21] However, even after the Coronary Primary Prevention Trial and the NIH Consensus Conference in the mid 80s, criticism persisted in a minority of the scientific community questioning the statistical and mechanistic significance of the associations measured in the trials and the conclusions of the panel.^[22]

In the following years, studies with lipid- and cholesterol-lowering drugs such as statins provided further associative evidence in support of the lipid hypothesis.^[23][24][25] This was questioned on the basis that the positive effect of statins may be due to other effects than cholesterol-lowering - a meta-analysis of cholesterol-lowering trials demonstrated that coronary mortality was not lowered by cholesterol lowering, but total mortality was increased.^[26] Further studies were designed in the hope of settling the controversy.^[27][28][29] The continuing consensus regards the lipid hypothesis as proven; but disagreement still persists among a small group who argue that it is based on associations and misrepresented or overinterpreted data, and has not been shown as a scientifically validated causal mechanism.^[16][30][31]

Palm oil and blood cholesterol controversy

Palm oil is a mix of about 50% saturated fatty acids (palmitic acid, stearic acid) with 50% unsaturated fatty acids (oleic acid, linoleic acid), supplemented with antioxidants, beta-carotene and vitamin E. While there is convincing evidence that palmitic and stearic acid contribute to an increased risk of developing cardiovascular diseases^[32], unsaturated fatty acids such as oleic and linoleic acid are effective in reducing serum total and low-density lipoprotein (LDL) cholesterol levels.^[33] Palm oil has a mixed effect: While consumption of palm oil leads to a higher blood cholesterol level compared to other vegetable oils, fresh palm oil leads to a reduction of endogenous cholesterol level and a reduced risk of arterial thrombosis and atherosclerosis.^[34] A study by a group of researchers in China comparing palm, soybean, peanut oils and lard showed that palm oil increased the levels of "good cholesterol" and reduced the levels of "bad cholesterol" in the blood.^[35] A study by Hornstra in 1990 also showed similar results.^[36] In contrast to fresh palm oil, oxidized (processed) palm oil has adverse effects on the lipid profile and contains toxic substances detrimental to health, e.g. by harming the liver.^[34]

Other lipid hypotheses

The Alzheimer's lipid hypothesis and cholesterol controversy

A new "cholesterol controversy" is emerging out of the research of the pathogenesis of Alzheimer's disease (AD). A "lipid hypothesis of AD" has been proposed that suggests a connection between cholesterol and changes in brain lipids found in Alzheimer-type neuropathology.^[37]

The lipid hypothesis of osteoporosis

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 preosteoblasts 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.^[38]

The lipid hypothesis of cold tolerance

In plants and microbes, changes in the lipid composition of cell membranes have been linked to cold tolerance.^[39] 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.^[40] 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,^[41] 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.^[42]

See also

• Atherosclerosis
• Cholesterol
• Hypercholesterolemia
• The International Network of Cholesterol Skeptics

Notes and references