Lipid hypothesis

The lipid hypothesis was one of two hypotheses (the other being the chronic endothelial injury hypothesis) developed in the 1850s to explain the pathogenesis of atherosclerosis. It proposes a connection between plasma cholesterol level and the development of coronary heart disease.

It was proposed by the German pathologist Rudolf Virchow in 1856 and suggested that blood lipid accumulation in arterial walls causes atherosclerosis.^{[citation needed][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.

Lipid hypothesis of atherogenesis

Early studies and origin

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:

Question	Yes	No	Uncertain
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.^[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] Critics point out that the standard for proof in the field is placebo controlled, double blind tests and not argumentum ad populum.^[16] A minority of the medical community still argue that the lipid hypothesis has not yet been scientifically validated as having identified a cause of heart disease.^[17][18][19]

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

Cholesterol controversy of atherogenesis

During the 1970s and 1980s, 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.^[20] Some skeptics were questioning its validity by arguing that the studies supporting it were flawed.^[21][22] 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.^[23] However, even after the Coronary Primary Prevention Trial^[24] and the NIH Consensus Conference in the mid 1980s, 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.^[25]

In the following years, studies with lipid- and cholesterol-lowering drugs such as statins provided further associative evidence in support of the lipid hypothesis.^{[26][27][28][29]} However, 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, considering 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.^[30] One proposed mechanism by which statins reduce coronary heart disease is by working as vitamin D analogues.^[31] Further studies were designed in the hope of settling the controversy.^[32][33][34] The continuing consensus regards the lipid hypothesis as proven; but disagreement still persists among groups who argue that it is based on associations and misrepresented or over-interpreted data, and has not been shown as a scientifically validated causal mechanism.^[17][35][36]

A documentary film titled Fat Head (2009) covers, in the second half of the movie, the origin and the propagation of the lipid hypothesis. The film chronicles the claims made by the main proponents of the lipid hypothesis, how their work influenced the nutrition guidelines published by the U.S. government, and the alleged lack of scientifically valid statistical evidence for those claims.

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 (but not stearic) acid contribute to an increased risk of developing cardiovascular diseases,^[37] unsaturated fatty acids such as oleic and linoleic acid are effective in reducing serum total and low-density lipoprotein (LDL) cholesterol levels.^[38] 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.^[39] 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.^[40] A study by Hornstra in 1990 also showed similar results.^[41] 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.^[39]

Other lipid hypotheses

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.^[42]

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.^[43]

Lipid hypothesis of cold tolerance

In plants and microbes, changes in the lipid composition of cell membranes have been linked to cold tolerance.^[44] 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.^[45] 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,^[46] 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.^[47]

See also

• Atherosclerosis
• Cholesterol
• Hypercholesterolemia
• Blood lipids
• The International Network of Cholesterol Skeptics
• Medical research related to low-carbohydrate diets

Notes and references

1. ^ Virchow, Rudolf (1856). "Gesammelte Abhandlungen zur wissenschaftlichen Medizin". Germany: Staatsdruckerei Frankfurt. Phlogose und Thrombose im Gefäßsystem. http://books.google.ca/books?id=rsRXAAAAMAAJ&dq=%22Gesammelte%20Abhandlungen%22%20%22zur%20wissenschaftlichen%20Medizin%22%201856&pg=RA5-PA47#v=onepage&q=%22Phlogose%22&f=false. 
2. ^ ^{a b} 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. 
3. ^ Anitschkow NN, Chatalov S (1913). "Über experimentelle Cholesterinsteatose und ihre Bedeutung für die Entstehung einiger pathologischer Prozesse". Zentralbl Allg Pathol 24: 1–9. 
4. ^ Anitschkow NN (1913). "Über die Veränderungen der Kaninchenaorta bei experimenteller Cholesterinsteatose". Beitr Pathol Anat 56: 379–404. 
5. ^ Duff GL, McMillian GC (1951). "Pathology of atherosclerosis". Am J Med 11 (1): 92–108. doi:10.1016/0002-9343(51)90011-3. PMID 14837929. 
6. ^ Keys A (1953). "Atherosclerosis: a problem in newer public health". Journal of the Mount Sinai Hospital, New York 20 (2): 118–39. PMID 13085148. 
7. ^ Keys, Ancel (1959). Eat Well and Stay Well. United States: Doubleday. ISBN 0385065752. 
8. ^ "Ancel Keys Obituary". The American Physiological Society. http://www.the-aps.org/membership/obituaries/ancel_keys.htm. Retrieved 2007-04-15. 
9. ^ Norum KR (1978). "Some present concepts concerning diet and prevention of coronary heart disease.". Nutr Metab 22 (1): 1–7. PMID 619310. 
10. ^ 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. 
11. ^ from NIH Consensus Development Conference, JAMA 1985, 253:2080
12. ^ Steinberg D (1989). "The cholesterol controversy is over. Why did it take so long?". Circulation 80 (4): 1070–1078. PMID 2676235. 
13. ^ LaRosa JC (1998). "Cholesterol & atherosclerosis: a controversy resolved". Adv Nurse Pract 6 (5): 36–37. PMID 9633288. 
14. ^ 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. 
15. ^ 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. 
16. ^ Taubes, Gary (2007). Good Calories, Bad Calories. United States: Knoph. ISBN 1400040787. 
17. ^ ^{a b} Ravnskov, Uffe (2000). The Cholesterol Myths: Exposing the Fallacy that Saturated Fat and Cholesterol cause Heart Disease. United States: New Trends Publishing. ISBN 0967089700. 
18. ^ "THINCS home page". The International Network of Cholesterol Skeptics. http://www.thincs.org. Retrieved 2007-04-15. 
19. ^ 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. http://www.nutritionandhealth.info/downloads/softsciencefat.pdf. 
20. ^ Rifkind B, Levy R (1978). "Testing the lipid hypothesis. Clinical trials". Archives of surgery (Chicago, Ill. : 1960) 113 (1): 80–3. PMID 619863. 
21. ^ Oliver M (1981). "Lipid lowering and ischaemic heart disease". Acta Med. Scand. Suppl. 651: 285–93. PMID 6948505. 
22. ^ Stehbens W (1988). "Flaws in the lipid hypothesis of atherogenesis". Pathology 20 (4): 395–6. doi:10.3109/00313028809085228. PMID 3241740. 
23. ^ Gotto AM Jr (1984). "Directions of atherosclerosis research in the 1980s and 1990s". Circulation 70 (5 Pt 2): III88–94. PMID 6488509. 
24. ^ "The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering". JAMA 251 (3): 365–74. 1984. doi:10.1001/jama.251.3.365. PMID 6361300. 
25. ^ Kolata G (1985). "Heart panel's conclusions questioned". Science 227 (4682): 40–1. doi:10.1126/science.3880617. PMID 3880617. 
26. ^ 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. PMID 9974397. http://atvb.ahajournals.org/cgi/content/full/19/2/187. 
27. ^ Tyroler HA (1987). "Review of lipid-lowering clinical trials in relation to observational epidemiologic studies". Circulation 76 (3): 515–522. PMID 3304704. 
28. ^ Brown WV (1990). "Review of clinical trials: proving the lipid hypothesis". Eur Heart J 11 Suppl H: 15–20. PMID 2073909. 
29. ^ 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. 
30. ^ 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. 
31. ^ David S Grimes, Are statins analogues of vitamin D?, The Lancet, Volume 368, Issue 9529, 1 July 2006-7 July 2006, Pages 83-86, ISSN 0140-6736, DOI: 10.1016/S0140-6736(06)68971-X.
32. ^ Pyrola K, Steiner G (1996). "Will correction of dyslipoproteinaemia reduce coronary heart disease risk in patients with non-insulin-dependent diabetes? Need for trial evidence". Ann Med 28 (4): 357–362. doi:10.3109/07853899608999093. PMID 8862691. 
33. ^ Steiner G (1996). "The Diabetes Atherosclerosis Intervention Study (DAIS): a study conducted in cooperation with the World Health Organization". Diabetologia 39 (12): 1655–1661. doi:10.1007/s001250050630. PMID 9081851. 
34. ^ Steiner G (2000). "Lipid intervention trials in diabetes". Diabetes Care 23 Suppl 2: B49–53. PMID 10860191. 
35. ^ 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. 
36. ^ 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. 
37. ^ "Diet, Nutrition and the Prevention of Chronic Diseases". World Health Organization. http://www.fao.org/DOCREP/005/AC911E/ac911e00.htm. Retrieved 2007-04-18.  - PDF (WHO Technical Report Series 916. Geneva. 2003. pages 82, 88 &c)
38. ^ Vessby B (1994). "Implications of long-chain fatty acid studies". INFORM 5: 182–185. 
39. ^ ^{a b} Edem D (2002). "Palm oil: biochemical, physiological, nutritional, hematological, and toxicological aspects: a review". Plant foods for human nutrition (Dordrecht, Netherlands) 57 (3–4): 319–41. doi:10.1023/A:1021828132707. PMID 12602939. 
40. ^ Zhang J, Ping W, Chunrong W, Shou C, Keyou G (1997). "Nonhypercholesterolemic effects of a palm oil diet in Chinese adults". J. Nutr. 127 (3): 509S–513S. PMID 9082037. 
41. ^ Hornstra G, van Houwelingen A, Kester A, Sundram K (1991). "A palm oil-enriched diet lowers serum lipoprotein(a) in normocholesterolemic volunteers". Atherosclerosis 90 (1): 91–3. doi:10.1016/0021-9150(91)90247-Z. PMID 1839208. 
42. ^ Kivipelto M, Solomon A, Blennow K, Olsson AG, Winblad B (2006). "The new cholesterol controversy - a little bit of history repeating?". Acta Neurol Scand 114 Suppl 185: 1–2. doi:10.1111/j.1600-0404.2006.00678.x. PMID 16866903. 
43. ^ 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.1999.14.12.2067. PMID 10620066. 
44. ^ 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. 
45. ^ Kodama, Kodama, Kodama, Kodama, Kodama (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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=159399. 
46. ^ 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. 
47. ^ 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. 

External links

• 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 0-12373-979-9.
  • An interpretive history of the cholesterol controversy: part I. PMID 15102877.
  • An interpretive history of the cholesterol controversy: part II: the early evidence linking hypercholesterolemia to coronary disease in humans. PMID 15547293.
  • An interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia. PMID 15995167.
  • An interpretive history of the cholesterol controversy, part IV: The 1984 Coronary Primary Prevention Trial ends it—almost. PMID 16227628.
  • An interpretive history of the cholesterol controversy, part V: The discovery of the statins and the end of the controversy. PMID 16585781.