The lipid hypothesis was described in 1976 as the premise that "measures used to lower the plasma lipids in patients with hyperlipidemia will lead to reductions in new events of coronary heart disease". Another formulation is that "decreasing blood cholesterol... significantly reduces coronary heart disease events"; this discussion is also referred to as the "cholesterol controversy". It is closely related to the saturated fat and cardiovascular disease controversy.
An accumulation of evidence has led to the acceptance of the lipid hypothesis as scientific fact by most of the medical community; however, a minority contends that the evidence does not support it, and that mechanisms independent of blood cholesterol levels are responsible.
Ideas to the mid-20th century
The German pathologist Rudolf 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.
From the 1940s
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 (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%. 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 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;
In 1978, 211 prominent researchers in the field were questioned about plasma cholesterol and the advisability of changing dietary habits. 90% responded, giving the following answers:
|Do you think there is a connection between plasma cholesterol level and the development of coronary heart disease?||189||2||2|
|Do you think that our knowledge about diet and coronary heart disease is sufficient to recommend a moderate change in the diet for the population of an affluent society?||176||16||1|
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. 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...—
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."
There was ongoing contention about the results and meaning of intervention studies undertaken before the introduction of statins.A meta-analysis of cholesterol-lowering trials found 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. This meta-analysis, including the less-cited trials, found that mortality was not decreased by lowering cholesterol, and that the lowering of cholesterol was unlikely to prevent coronary heart disease. Uffe Ravnskov, director of The International Network of Cholesterol Skeptics, maintains that "prominent scientists have turned white into black by ignoring all conflicting observations; by twisting and exaggerating trivial findings; by citing studies with opposing results in a way to make them look supportive; and by ignoring or scorning the work of critical scientists." 
In particular, Keys' supplementary hypothesis that reducing saturated fat in the diet will reduce cardiovascular disease has been described 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".
Other biological lipid hypotheses
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 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.
- Blood lipids
- The International Network of Cholesterol Skeptics
- Medical research related to low-carbohydrate diets
Notes and references
- Ann Intern Med. 1976 Jul;85(1):87-93. The management of hyperlipidemia: whether, rather than how. Ahrens EH Jr. http://www.ncbi.nlm.nih.gov/pubmed/779574
- Steinberg D (2006). "An interpretive history of the cholesterol controversy, part IV: The 1984 coronary primary prevention trial ends it - almost". J Lipid Res 47 (1): 1–14. doi:10.1194/jlr.R500014-JLR200. PMID 16227628.
- Gotto AM Jr (1984). "Directions of atherosclerosis research in the 1980s and 1990s". Circulation 70 (5 Pt 2): III88–94. PMID 6488509.
- Steinberg D (2006). "Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part V: the discovery of the statins and the end of the controversy". J. Lipid Res. 47 (7): 1339–51. doi:10.1194/jlr.R600009-JLR200. PMID 16585781.
- Ravnskov, Uffe (2000). The Cholesterol Myths: Exposing the Fallacy that Saturated Fat and Cholesterol cause Heart Disease. United States: New Trends Publishing. ISBN 0-9670897-0-0.
- Taubes G (March 2001). "Nutrition. The soft science of dietary fat". Science 291 (5513): 2536–45. doi:10.1126/science.291.5513.2536. PMID 11286266.
- Virchow, Rudolf (1856). "Gesammelte Abhandlungen zur wissenschaftlichen Medizin". Vierteljahrschrift für die praktische Heilkunde (Germany: Staatsdruckerei Frankfurt). Phlogose und Thrombose im Gefäßsystem.
- Anitschkow NN, Chatalov S (1913). "Über experimentelle Cholesterinsteatose und ihre Bedeutung für die Entstehung einiger pathologischer Prozesse". Zentralbl Allg Pathol 24: 1–9.
- Anitschkow NN (1913). "Über die Veränderungen der Kaninchenaorta bei experimenteller Cholesterinsteatose". Beitr Pathol Anat 56: 379–404.
- Duff GL, McMillan GC (1951). "Pathology of atherosclerosis". Am J Med 11 (1): 92–108. doi:10.1016/0002-9343(51)90011-3. PMID 14837929.
- Keys A, Taylor HL, Blackburn H, Brozek J, Anderson JT, Simonson E. Circulation. 1963 Sep;28:381-95.
- Yerushalmy J, Hilleboe HE. Fat in the diet and mortality from heart disease. A methodologic note. NY State J Med 1957;57:2343–54.
- Keys A (Ed). Seven Countries: A multivariate analysis of death and coronary heart disease. Harvard University Press. Cambridge, Massachusetts. 1980. ISBN 0-674-80237-3.
- Keys, Ancel (1959). Eat Well and Stay Well. United States: Doubleday. ISBN 0-385-06575-2.
- "Ancel Keys Obituary". The American Physiological Society. Retrieved 2007-04-15.
- Norum KR (1978). "Some present concepts concerning diet and prevention of coronary heart disease.". Nutr Metab 22 (1): 1–7. doi:10.1159/000176192. PMID 619310.
- from NIH Consensus Development Conference, JAMA 1985, 253:2080
- Steinberg D (1989). "The cholesterol controversy is over. Why did it take so long?". Circulation 80 (4): 1070–1078. doi:10.1161/01.cir.80.4.1070. PMID 2676235.
- LaRosa JC (1998). "Cholesterol & atherosclerosis: a controversy resolved". Adv Nurse Pract 6 (5): 36–37. PMID 9633288.
- Steinberg D (2002). "Atherogenesis in perspective: hypercholesterolemia and inflammation as partners in crime". Nature Medicine 8 (11): 1211–1217. doi:10.1038/nm1102-1211. PMID 12411947.
- Thompson GR, Packard CJ, Stone NJ (2002). "Goals of statin therapy: three viewpoints". Curr Atheroscler Rep 4 (1): 26–33. doi:10.1007/s11883-002-0059-6. PMID 11772419.
- Bucher, HC; Griffith, LE; Guyatt, GH (February 1999). "Systematic review on the risk and benefit of different cholesterol-lowering interventions". Arteriosclerosis Thrombosis and Vascular Biology 19 (2): 187–195. doi:10.1161/01.atv.19.2.187. PMID 9974397.
- Tyroler HA (1987). "Review of lipid-lowering clinical trials in relation to observational epidemiologic studies". Circulation 76 (3): 515–522. doi:10.1161/01.cir.76.3.515. PMID 3304704.
- Brown WV (1990). "Review of clinical trials: proving the lipid hypothesis". Eur Heart J. 11 Suppl H: 15–20. doi:10.1093/eurheartj/11.suppl_h.15. PMID 2073909.
- Kroon AA, Stalenhoef AF (1997). "LDL-cholesterol lowering and atherosclerosis -- clinical benefit and possible mechanisms: an update". Neth J Med 51 (1): 16–27. doi:10.1016/S0300-2977(97)00031-4. PMID 9260486.
- Rifkind B, Levy R (1978). "Testing the lipid hypothesis. Clinical trials". Archives of surgery (Chicago, Ill. : 1960) 113 (1): 80–3. doi:10.1001/archsurg.1978.01370130082014. PMID 619863.
- Oliver M (1981). "Lipid lowering and ischaemic heart disease". Acta Med. Scand. Suppl. 651: 285–93. PMID 6948505.
- Stehbens W (1988). "Flaws in the lipid hypothesis of atherogenesis". Pathology 20 (4): 395–6. doi:10.3109/00313028809085228. PMID 3241740.
- Kolata G (1985). "Heart panel's conclusions questioned". Science 227 (4682): 40–1. doi:10.1126/science.3880617. PMID 3880617.
- Ravnskov Uffe (1992). "Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome". British Medical Journal 305 (6844): 15–19, 420–422, 717. doi:10.1136/bmj.305.6844.15.
- Stehbens WE (2001). "Coronary heart disease, hypercholesterolemia, and atherosclerosis I. False premises". Exp Mol Pathol 70 (2): 103–119. doi:10.1006/exmp.2000.2340. PMID 11263954.
- Stehbens WE (2001). "Coronary heart disease, hypercholesterolemia, and atherosclerosis II. Misrepresented data". Exp Mol Pathol 70 (2): 120–139. doi:10.1006/exmp.2000.2339. PMID 11263955.
- The Cholesterol Myths by Uffe Ravnskov, MD, PhD. http://www.ravnskov.nu/uffe.htm accessed 3 March 2014
- Association of Dietary, Circulating, and Supplement Fatty Acids With Coronary Risk: A Systematic Review and Meta-analysis. Rajiv Chowdhury, MD, PhD; Samantha Warnakula, MPhil; Setor Kunutsor, MD, MSt; Francesca Crowe, PhD; Heather A. Ward, PhD; Laura Johnson, PhD; Oscar H. Franco, MD, PhD; Adam S. Butterworth, PhD; Nita G. Forouhi, MRCP, PhD; Simon G. Thompson, FMedSci; Kay-Tee Khaw, FMedSci; Dariush Mozaffarian, MD, DrPH; John Danesh, FRCP*; and Emanuele Di Angelantonio, MD, PhD. Annals of Internal Medicine. 2014;160(6):398-406-406. doi:10.7326/M13-1788
- Parhami F, Jackson SM, Tintut Y, Le V, Balucan JP, Territo M, Demer LL (1999). "Atherogenic diet and minimally oxidized low density lipoprotein inhibit osteogenic and promote adipogenic differentiation of marrow stromal cells". J. Bone Miner. Res. 14 (12): 2067–78. doi:10.1359/jbmr.1922.214.171.1247. PMID 10620066.
- Finegold L (1986). "Molecular aspects of adaptation to extreme cold environments". Adv Space Res 6 (12): 257–64. doi:10.1016/0273-1177(86)90094-3. PMID 11537829.
- H. Kodama, T. Hamada, G. Horiguchi, M. Nishimura, and K. Iba (1994). "Genetic Enhancement of Cold Tolerance by Expression of a Gene for Chloroplast [omega]-3 Fatty Acid Desaturase in Transgenic Tobacco". Plant physiology 105 (2): 601–605. PMC 159399. PMID 12232227.
- Ohtsu T, Kimura M, Katagiri C (1998). "How Drosophila species acquire cold tolerance--qualitative changes of phospholipids". Eur. J. Biochem. 252 (3): 608–11. doi:10.1046/j.1432-1327.1998.2520608.x. PMID 9546680.
- Hayward S, Murray P, Gracey A, Cossins A (2007). Beyond the Lipid Hypothesis. "Beyond the lipid hypothesis: mechanisms underlying phenotypic plasticity in inducible cold tolerance". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology 594: 132–42. doi:10.1007/978-0-387-39975-1_12. ISBN 978-0-387-39974-4. PMID 17205681.
- A 5-part history of the lipid hypothesis and the "cholesterol controversy" by Daniel Steinberg, published in the Journal of Lipid Research in 2004–2006. These are condensed from his The Cholesterol Wars. Academic Press, 2007. ISBN 0-12-373979-9.
- Steinberg D (September 2004). "Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I". J. Lipid Res. 45 (9): 1583–93. doi:10.1194/jlr.R400003-JLR200. PMID 15102877..
- Steinberg D (February 2005). "Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans". J. Lipid Res. 46 (2): 179–90. doi:10.1194/jlr.R400012-JLR200. PMID 15547293..
- Steinberg D (October 2005). "Thematic review series: the pathogenesis of atherosclerosis: an interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia". J. Lipid Res. 46 (10): 2037–51. doi:10.1194/jlr.R500010-JLR200. PMID 15995167..
- Steinberg D (January 2006). "The pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part IV: the 1984 coronary primary prevention trial ends it--almost". J. Lipid Res. 47 (1): 1–14. doi:10.1194/jlr.R500014-JLR200. PMID 16227628..
- Steinberg D (July 2006). "Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part V: the discovery of the statins and the end of the controversy". J. Lipid Res. 47 (7): 1339–51. doi:10.1194/jlr.R600009-JLR200. PMID 16585781..