Reverse cholesterol transport

Reverse cholesterol transport is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver first via entering the lymphatic system, then the bloodstream. ^[1]

• HDL is first produced in the liver in a cholesterol-free form. As a result, it appears discoidal in shape. This is called a Discoidal (Nascent) HDL particle.
• Cholesterol from non-hepatic peripheral tissues is transferred to HDL by the ABCA1 (ATP-binding cassette transporter). ^[2] Apolipoprotein A1 (ApoA-1), the major protein component of HDL, acts as an acceptor, and the phospholipid component of HDL acts as a sink for the mobilised cholesterol.
  • In atherosclerosis, much emphasis is placed on macrophages. Macrophages use both ABCA1 and ABCG1 to send cholesterol to HDL particles. ^[3]
• The cholesterol is converted to cholesteryl esters by the enzyme LCAT (lecithin-cholesterol acyltransferase) for storage.
  • The cholesteryl esters can be transferred, with the help of CETP (cholesterylester transfer protein) in exchange for triglycerides, to ApoB-containing lipoproteins (LDL, VLDL, IDL). These other lipoproteins can be eventually taken up by the liver through their own receptors – an alternate route for liver uptake – or end up transporting the cholesterol back to the tissues.
• When the HDL particle is cholesterol-rich, its shape is changed into more spherical and it becomes less dense (HDL 2). This is carried to the liver to release all the esterified cholesterol into the liver. Uptake of HDL₂ is mediated by hepatic lipase, a special form of lipoprotein lipase found only in the liver. Hepatic lipase activity is increased by androgens and decreased by estrogens, which may account for higher concentrations of HDL₂ in women. SR-BI also plays a facilitating role. ^[4]
• After the liver receives the cholesterol, it can secrete them into bile juice in the form of bile acids. Some of these bile acids is eliminated via feces, while the rest is absorbed by the intestines. ^[3] Enzymes involved in bile acid secretion include ABCG5 and ABCG8. ^[5]

Regulation

Adiponectin induces ABCA1-mediated reverse cholesterol transport from macrophages by activation of PPAR-γ and LXRα/β. ^[6]

Estimating transport ability

Traditionally the amount of HDL-C is used as a proxy to measure the amount of HDL particles, and from there a proxy for the reverse cholesterol transport capacity. However, a number of conditions that increase reverse cholesterol transport (e.g. being male) will reduce HDL-C due to the greater clearance of HDL, making such a test unreliable. In fact, when many known correlates of CVD risks are controlled for, HDL-C does not have any correlation with cardiovascular event risks. In this way, HDL-C only seems to serve as an imperfect, but easy-to-measure, proxy for a healthy lifestyle. ^[7]

The actual cholesterol efflux capacity (CEC) is measured directly: one takes a blood sample from the patient, isolates the serum, and removes any ApoB-containg particles from it. Mouse macrophages are incubated in an ACAT inhibitor and radioisotope-labelled cholesterol, then have their efflux ability "woken up" with an ABCA1 agonist before use. They are then mixed with the prepared serum. The macrophages are then recovered to quantify their change in radioactivity compared to a control batch. Any extra loss in radioactivity is interpreted to have been taken up by the HDL particles in the patient's serum. ^[8] (This test does not account for the liver-bile-feces part of the transport.)

Clinical relevance

The cholesterol efflux capacity (CEC) has much better correlation with CVD risks and CVD event frequencies, even when controlling for known correlates. ^[7] Many drugs affect enzymes and receptors involved in the transport process:

• Nicotinic acid (niacin) lowers LDL-C and increases HDL-C. It does not lower the risk of cardiovascular events. ^[9] It stimulates ABCA1 ^[10] but inhibits hepatic uptake through the CETP route. ^[11] It also increases ApoA-I levels by preventing its breakdown. ^[12] It has minimal effects on CEC. ^[13]
• Some CETP inhibitors have been made to try and increase HDL-C. However, they end up reducing reverse transport and increasing cardiovascular risks. ^[7] A 2016 source says that they increase non-ABCA1-mediated CEC. ^[13]
• Fibrates activate PPAR-α, which as a result upregulates ABCA1, ABCG5, and ABCG8. ^[5] Not all of them have shown expected improvements when combined with a statin. ^[7] Fenofibrate appears to have better cardiovascular outcomes than some other fibrates. Part of that may be because gemfibrozil increases the breakdown of ApoA-I. In mice, fenofibrate increases macrophage-to-feces reverse transport, while gemfibrozil does not. ^[5]
• Probucol decreases LDL-C but, alarmingly, also HDL-C. It promotes LDL uptake, inhibits ABCA1, enhances CETP, and enhances SR-BI. The net effect is an increase in reverse transport. ^[14]
• Statins either have minimal effects on CEC or slightly decrease it. Statins are known to reduce CV risks. ^[13]
• Exogenous Apo A-I, several forms of which are being developed as medication, increase CEC. Another drug in development increases the body's production of Apo A-I. Their effects on CV risks are being studied. ^[13]
• The effects of diabetes medication on CEC are poorly studied. There is only information of pioglitazone, which seems to increase CEC. ^[13]
• Diet and exercise have little effect on CEC among non-atheltes. In atheletes it seems to increase a little together with Apo A-I and HDL-C. ^[13]

References

1. Huang, LH; Elvington, A; Randolph, GJ (September 2015). "The role of the lymphatic system in cholesterol transport". Frontiers in Pharmacology. 6 (182): 182. doi: 10.3389/fphar.2015.00182 . PMC   4557107 . PMID   26388772.
2. http://biochemistry.med.uoc.gr/photos/kardasis_research-07.gif in
3. Rader, Daniel J.; Alexander, Eric T.; Weibel, Ginny L.; Billheimer, Jeffrey; Rothblat, George H. (April 2009). "The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis". Journal of Lipid Research. 50 (Suppl): S189 –S194. doi: 10.1194/jlr.R800088-JLR200 . PMC   2674717 . PMID   19064999.
4. Rhainds D, Brissette L (January 2004). "The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. defining the rules for lipid traders". The International Journal of Biochemistry & Cell Biology. 36 (1): 39–77. doi:10.1016/s1357-2725(03)00173-0. PMID   14592533.
5. Rotllan, Noemí; Llaverías, Gemma; Julve, Josep; Jauhiainen, Matti; Calpe-Berdiel, Laura; Hernández, Cristina; Simó, Rafael; Blanco–Vaca, Francisco; Escolà-Gil, Joan Carles (February 2011). "Differential effects of gemfibrozil and fenofibrate on reverse cholesterol transport from macrophages to feces in vivo". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1811 (2): 104–110. doi:10.1016/j.bbalip.2010.11.006. PMID   21126601.
6. Hafiane A, Gasbarrino K, Daskalopoulou SS (2019). "The role of adiponectin in cholesterol efflux and HDL biogenesis and metabolism". Metabolism: Clinical and Experimental . 100: 153953. doi:10.1016/j.metabol.2019.153953. PMID   31377319. S2CID   203413137.
7. Razavi, AC; Jain, V; Grandhi, GR; Patel, P; Karagiannis, A; Patel, N; Dhindsa, DS; Liu, C; Desai, SR; Almuwaqqat, Z; Sun, YV; Vaccarino, V; Quyyumi, AA; Sperling, LS; Mehta, A (18 January 2024). "Does Elevated High-Density Lipoprotein Cholesterol Protect Against Cardiovascular Disease?". The Journal of Clinical Endocrinology and Metabolism. 109 (2): 321–332. doi:10.1210/clinem/dgad406. PMC   11032254 . PMID   37437107.
8. Khera, AV; Cuchel, M; de la Llera-Moya, M; Rodrigues, A; Burke, MF; Jafri, K; French, BC; Phillips, JA; Mucksavage, ML; Wilensky, RL; Mohler, ER; Rothblat, GH; Rader, DJ (13 January 2011). "Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis". The New England Journal of Medicine. 364 (2): 127–35. doi:10.1056/NEJMoa1001689. PMC   3030449 . PMID   21226578.
9. Schandelmaier S, Briel M, Saccilotto R, Olu KK, Arpagaus A, Hemkens LG, Nordmann AJ (June 2017). "Niacin for primary and secondary prevention of cardiovascular events". The Cochrane Database of Systematic Reviews. 2017 (6): CD009744. doi:10.1002/14651858.CD009744.pub2. PMC   6481694 . PMID   28616955.
10. Rubic T, Trottmann M, Lorenz RL (February 2004). "Stimulation of CD36 and the key effector of reverse cholesterol transport ATP-binding cassette A1 in monocytoid cells by niacin". Biochemical Pharmacology. 67 (3): 411–9. doi:10.1016/j.bcp.2003.09.014. PMID   15037193.
12. Malik S, Kashyap ML (November 2003). "Niacin, lipids, and heart disease". Curr Cardiol Rep. 5 (6): 470–6. doi:10.1007/s11886-003-0109-x. PMID   14558989. S2CID   27918392.
13. Brownell, N; Rohatgi, A (August 2016). "Modulating cholesterol efflux capacity to improve cardiovascular disease". Current Opinion in Lipidology. 27 (4): 398–407. doi:10.1097/MOL.0000000000000317. PMID   27213627.
14. Yamashita S, Masuda D, Matsuzawa Y (August 2015). "Did we abandon probucol too soon?". Current Opinion in Lipidology. 26 (4): 304–16. doi:10.1097/MOL.0000000000000199. PMID   26125504.