Cholesterol is a sterol, a type of lipid that makes up an essential component of all cell membranes.1 It plays a myriad of important functions in the body, ranging from cellular membrane physiology and dietary nutrient absorption to reproductive functions and stress responses. These nonpolar lipid molecules require lipoprotein particles to transport them in the plasma. There are five different classes of plasma lipoproteins: chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL).
The Framingham Heart study was the first to recognize that high total serum cholesterol levels were associated with an increased risk of heart disease.2 Subsequent analysis of the same cohort recognized that high-density lipoprotein cholesterol (HDL-C) had an inverse relationship with coronary heart disease risk, providing a protective effect, while low-density lipoprotein cholesterol (LDL-C) increased the risk of coronary heart disease.3 Thus began the differentiation of “good” and “bad” cholesterol.
In the years since this observation, a better understanding of the mechanism of HDL’s cardioprotective effects has emerged.4 The beneficial effect of HDL-C is generally thought to be related to its role in transporting excess cholesterol back to the liver, so-called reverse cholesterol transport. In addition, HDL-C has been shown to have anti-inflammatory,5,6 anti-oxidative, and vasodilatory effects8,9 that may also contribute to its cardioprotective quality.
Despite these observations, efforts to increase HDL-C levels with medication have not yet proved to be as effective in lowering cardiovascular disease risk as has lowering LDL-C with statins.10–12 More recent studies are targeting aspects of the HDL-C functionality in reverse cholesterol transport rather than HDL-C levels, but evidence for an effective treatment that is proven to lower cardiovascular risk is not yet strong.13,14
References
- Tabas I. Cholesterol in health and disease. J Clin Invest. 2002;110(5):583-590.
- Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J. Factors of risk in the development of coronary heart disease--six year follow-up experience. The Framingham Study. Ann Intern Med. 1961;55:33-50.
- Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977;62(5):707-714.
- Nagao M, Nakajima H, Toh R, Hirata K-I, Ishida T. Cardioprotective effects of high-density lipoprotein beyond its anti-atherogenic action. J Atheroscler Thromb. 2018;25(10):985-993.
- Kasikara C, Doran AC, Cai B, Tabas I. The role of non-resolving inflammation in atherosclerosis. J Clin Invest. 2018;128(7):2713-2723.
- Levine DM, Parker TS, Donnelly TM, Walsh A, Rubin AL. In vivo protection against endotoxin by plasma high density lipoprotein. Proc Natl Acad Sci USA. 1993;90(24):12040-12044.
- Nagao M, Toh R, Irino Y, et al. High-density lipoprotein protects cardiomyocytes from oxidative stress via the PI3K/mTOR signaling pathway. FEBS Open Bio. 2017;7(9):1402-1409.
- Levkau B, Hermann S, Theilmeier G, et al. High-density lipoprotein stimulates myocardial perfusion in vivo. Circulation. 2004;110(21):3355-3359.
- Nofer J-R, van der Giet M, Tölle M, et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest. 2004;113(4):569-581.
- Sorci-Thomas MG, Thomas MJ. Why targeting HDL should work as a therapeutic tool, but has not. J Cardiovasc Pharmacol. 2013;62(3):239-246.
- AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-2267.
- Effect of fenofibrate on progression of coronary-artery disease in type 2 diabetes: the Diabetes Atherosclerosis Intervention Study, a randomised study. Lancet. 2001;357(9260):905-910.
- Favari E, Thomas MJ, Sorci-Thomas MG. High-density lipoprotein functionality as a new pharmacological target on cardiovascular disease: unifying mechanism that explains high-density lipoprotein protection toward the progression of atherosclerosis. J Cardiovasc Pharmacol. 2018;71(6):325-331.
- Ganjali S, Dallinga-Thie GM, Simental-Mendía LE, Banach M, Pirro M, Sahebkar A. HDL functionality in type 1 diabetes. Atherosclerosis. 2017;267:99-109.
