So your latest blood test results have come in, and you see a couple of numbers for cholesterol. What do those numbers mean, and why do we care about them? In this first part of our cholesterol miniseries, we break down the science behind this compound and trace how we made the link between certain types of cholesterol and heart disease. First, we follow the path that cholesterol takes in our bodies and what LDL and HDL mean in the context of heart disease. Then we delve into the history of this compound, which involves an over 2 billion year journey back in time, fascinating experiments that revealed the stubborn nature of medicine, and a terrible – but hopefully memorable – baseball analogy. Tune in for the low down on cholesterol.
| History | Biology |
| Bloch, Konrad. “The biological synthesis of cholesterol.” Science 150.3692 (1965): 19-28. | Luo, J., Yang, H. and Song, B.L., 2020. Mechanisms and regulation of cholesterol homeostasis. Nature reviews Molecular cell biology, 21(4), pp.225-245. |
| Bloch, Konrad. “Cholesterol: evolution of structure and function.” New comprehensive biochemistry. Vol. 20. Elsevier, 1991. 363-381. | Maxfield, F.R. and Tabas, I., 2005. Role of cholesterol and lipid organization in disease. Nature, 438(7068), pp.612-621. |
| Brown, Andrew J., and Anne M. Galea. “Cholesterol as an evolutionary response to living with oxygen.” Evolution 64.7 (2010): 2179-2183. | Simons, K. and Ikonen, E., 2000. How cells handle cholesterol. Science, 290(5497), pp.1721-1726. |
| Chaudhuri, Arunima, and Deepak Anand. “Cholesterol: Revisiting its fluorescent journey on 200th anniversary of Chevruel’s “cholesterine”.” Biomedical Spectroscopy and Imaging 6.1-2 (2017): 1-24. | Holmes, M.V. and Ala-Korpela, M., 2019. What is ‘LDL cholesterol’?. Nature Reviews Cardiology, 16(4), pp.197-198. |
| Galea, Anne M., and Andrew J. Brown. “Special relationship between sterols and oxygen: were sterols an adaptation to aerobic life?.” Free Radical Biology and Medicine 47.6 (2009): 880-889. | Cortes, V.A., Busso, D., Maiz, A., Arteaga, A., Nervi, F. and Rigotti, A., 2014. Physiological and pathological implications of cholesterol. Front Biosci (Landmark Ed), 19(3), pp.416-28. |
| Goldstein, Joseph L., and Michael S. Brown. “The LDL receptor.” Arteriosclerosis, thrombosis, and vascular biology 29.4 (2009): 431-438. | Duran, E.K., Aday, A.W., Cook, N.R., Buring, J.E., Ridker, P.M. and Pradhan, A.D., 2020. Triglyceride-rich lipoprotein cholesterol, small dense LDL cholesterol, and incident cardiovascular disease. Journal of the American College of Cardiology, 75(17), pp.2122-2135. |
| Klimov, Anatoli N., and Vladimir A. Nagornev. “Evolution of cholesterol concept of atherogenesis from Anitchkov to our days.” Pediatric Pathology & Molecular Medicine 21.3 (2002): 307-320. | Tabas, I., 2002. Cholesterol in health and disease. The Journal of clinical investigation, 110(5), pp.583-590. |
| Laufs, Ulrich, et al. “Why is hypercholesterolaemia so prevalent? A view from evolutionary medicine.” European Heart Journal 40.33 (2019): 2825-2830. | Castañer, O., Pintó, X., Subirana, I., Amor, A.J., Ros, E., Hernáez, Á., Martínez-González, M.Á., Corella, D., Salas-Salvadó, J., Estruch, R. and Lapetra, J., 2020. Remnant cholesterol, not LDL cholesterol, is associated with incident cardiovascular disease. Journal of the American College of Cardiology, 76(23), pp.2712-2724. |
| Luna-Reyes, Ismael, et al. “Cholesterol: an ancient ally or modern menace?.” Royal Society Open Science 13.3 (2026). | Sniderman, A.D., Glavinovic, T. and Thanassoulis, G., 2022. Key questions about familial hypercholesterolemia: JACC review topic of the week. Journal of the American College of Cardiology, 79(10), pp.1023-1031. |
| Mouritsen, Ole G., and Martin J. Zuckermann. “What’s so special about cholesterol?.” Lipids 39.11 (2004): 1101-1113. | Frąk, W., Wojtasińska, A., Lisińska, W., Młynarska, E., Franczyk, B. and Rysz, J., 2022. Pathophysiology of cardiovascular diseases: new insights into molecular mechanisms of atherosclerosis, arterial hypertension, and coronary artery disease. Biomedicines, 10(8), p.1938. |
| Olson, Robert E. “Discovery of the lipoproteins, their role in fat transport and their significance as risk factors.” The Journal of nutrition 128.2 (1998): 439S-443S. | Ajoolabady, A., Pratico, D., Lin, L., Mantzoros, C.S., Bahijri, S., Tuomilehto, J. and Ren, J., 2024. Inflammation in atherosclerosis: pathophysiology and mechanisms. Cell death & disease, 15(11), p.817. |
| Schekman, Randy. “Discovery of the cellular and molecular basis of cholesterol control.” Proceedings of the National Academy of Sciences 110.37 (2013): 14833-14836. | Song, Y., Liu, J., Zhao, K., Gao, L. and Zhao, J., 2021. Cholesterol-induced toxicity: an integrated view of the role of cholesterol in multiple diseases. Cell metabolism, 33(10), pp.1911-1925. |
| Steinberg, Daniel. “The cholesterol controversy is over. Why did it take so long?.” Circulation 80.4 (1989): 1070-1078. | Shobab, L.A., Hsiung, G.Y.R. and Feldman, H.H., 2005. Cholesterol in Alzheimer’s disease. The Lancet Neurology, 4(12), pp.841-852. |
| Steinberg, Daniel. “Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I.” Journal of lipid research 45.9 (2004): 1583-1593. | Libby, P., Ridker, P.M., Hansson, G.K. and Leducq Transatlantic Network on Atherothrombosis, 2009. Inflammation in atherosclerosis: from pathophysiology to practice. Journal of the American college of cardiology, 54(23), pp.2129-2138. |
| Steinberg, Daniel. “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.” Journal of lipid research 46.2 (2005): 179-190. | |
| Steinberg, Daniel. “An interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia.” J Lipid Res 46.10 (2005): 2037-2051. | |
| Steinberg, Daniel. “Thematic review series: The Pathogenesis of Atherosclerosis. An interpretive history of the cholesterol controversy, part IV: The 1984 Coronary Primary Prevention Trial ends it—almost1.” Journal of Lipid Research 47.1 (2006): 1-14. | |
| Steinberg, Daniel. “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.” Journal of lipid research 47.7 (2006): 1339-1351. | |
| Tabas, Ira. “Cholesterol in health and disease.” The Journal of clinical investigation 110.5 (2002): 583-590. | |
| Zetterström, Rolf. “The 1964 Nobel Prize for the discovery of the biosynthesis of cholesterol.” Acta paediatrica 98.7 (2009). | |
| Zhang, Tingting, et al. “Evolution of the cholesterol biosynthesis pathway in animals.” Molecular Biology and Evolution 36.11 (2019): 2548-2556. | |
| Zuniga-Hertz, Juan Pablo, and Hemal H. Patel. “The evolution of cholesterol-rich membrane in oxygen adaption: the respiratory system as a model.” Frontiers in Physiology 10 (2019): 1340. |
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