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High-Density Lipoprotein (HDL-C)

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High-Density Lipoprotein (HDL-C)

High-density lipoprotein (HDL) particles, characterized either in terms of cholesterol content or by the major protein constituent, apolipoprotein A-I (apoA-I), have been shown to be inversely related to risk of cardiovascular disease (CVD). In fact studies going back into the 1970s and even earlier indicate that the HDL particles are more strongly predictive of CVD risk than even the atherogenic LDL particles. Several mechanisms by which HDL provides cardioprotection have been proposed. One that is widely supported and accepted is reverse cholesterol transport (RCT), or more specifically macrophage RCT, whereby cholesterol is removed from sterol-laden arterial wall macrophages (foam cells). This mechanism helps the body clear excess cholesterol from the arterial wall. By RCT, excess cholesterol is collected in the periphery and transported back to the liver where it can be used for other processes or excreted to the biliary system as either free cholesterol or bile acids. Illustrated above is a schematic model of some of the complexities of cholesterol trafficking as mediated by HDLs. HDLs do not contain apolipoprotein B (apoB); rather, their main structural apoprotein is apoA-I. ApoA-I is synthesized by the liver and small intestine and released into the circulation as lipid-poor apoA-I. Through interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), phospholipids and free cholesterol are transferred to the nascent apoA-1 and mobilized into the plasma compartment. The newly synthesized, lipid-poor apoA-I interacts with ABCA1, sequestering excess cellular cholesterol and forming pre-β–HDL. Although any cell can upregulate ABCA1 and lipidate immature HDL species, the vast majority of HDL lipidation occurs in the liver and the small intestine. HDL lipidation by the arterial wall macrophage is termed macrophage RCT and is thought to be a major mechanism by which HDLs can be cardioprotective. As pre-β–HDL circulates through the blood stream interacting with the enzyme lecithin: cholesterol acyltransferase (LCAT). LCAT is responsible for the esterification of free cholesterol particles on the pre-β–HDL surface, converting it cholesteryl ester, which migrates to the core of the particle, transforming the HDL into a small but maturing α-HDL4 and α-HDL3 (also called HDL3). Lipid-poor apoA-I may be incorporated directly into pre-existing, small spherical HDLs that consequently expand because of their interaction with LCAT. Additional free cholesterol is transferred to the maturing HDL particles through the ATP-binding cassette sub-family G member 1 (ABCG1) transporter, resulting in an even more mature, large HDL termed α-HDL2, and α-HDL1 (also called HDL2), the most maximally lipidated HDL. Therefore HDL2, which can be considered the product of RCT, includes the larger and cholesterol enriched particles, whereas HDL-3 contains relatively less cholesterol. HDL2 can thus be considered to represent the more cardioprotective of the HDL subclasses. The fate of the lipids in HDL2, which are primarily cholesterol esters, involve multiple pathways:

  1. Cholesteryl esters (CE) in HDL can be trafficked directly to steroidogenic tissues (adrenal, gonads) or adipocytes. Alternatively the HDL can deliver its CE to the liver where it can be delipidated or endocytosed or to the small intestine where delipidation can also occur. The receptor that delipidates mature HDLs is the scavenger receptor B1 (SR-B1) and hepatic receptors capable of endocytosing HDLs are the holoparticle receptor (beta chain apoA-I synthase) or the LDL receptor which binds to apoE on HDLs. When HDLs traffic CE to the liver or intestine the process is called direct RCT.
  2. CE in HDL can also be transferred by means of CETP to other HDL species, or to VLDL or LDL in exchange for triglycerides (TG). Through this pathway, HDL-collected cholesterol from peripheral cells or the arterial wall is eventually transported to the liver via LDL and this process is termed indirect RCT.1 Total RCT is the sum of indirect and direct RCT. Because this is an ongoing, dynamic process in which HDLs are constantly being lipidated and delipidated, and exchanging core lipids, a serum HDL-C has no relationship to the process. Indeed, the last phase of RCT is delipidation of large HDLs.
  3. TG-rich HDL particles may interact with the hepatic lipase enzyme, or hepatic endothelial cell lipase (HEL), which catabolizes some of the core lipids in HDL2, thereby converting the larger HDL2 to smaller HDL3, which are then returned to the circulation for relipidation.4 HDLs lipidate and delipidate multiple times over their six day half-life.
  4. HDL may have additional functions, unrelated to RCT, that play a role in its potential anti-atherogenic effect; these are likely related to its proteome. HDL carries many proteins that perform a multitude of functions. Some HDL-associated proteins may decrease LDL oxidation and potentially have other antioxidant functions. HDLs also appear to stimulate the synthesis of leukocyte adhesion molecules in endothelial cells by supplying them with arachidonic acid.6 These unique functions are discussed in more detail in the later section on HDL2.

Clinical Interpretation

Studies indicate that low HDL-C levels are relatively common in the general population, with reported rates of HDL-C < 40 mg/dL (to convert to mmol/L, multiply by 0.0259) of 16% to 18% in men and 3% to 6% in women. In addition, a low level of HDL-C is a component of the metabolic syndrome, which has a prevalence of 34% in US individuals older than 20 years.

Multiple epidemiologic studies have established a low level of HDL-C as an independent risk factor for CVD.7,10 For example, in the Framingham Heart Study, 43% to 44% of coronary events occurred in persons with HDL-C levels < 40 mg/dL (22% of the total study population).7 Individuals having HDL-C levels < 35 mg/dL, had an eightfold higher incidence of CVD compared with those having HDL-C levels of > 65 mg/dL.7,10 The strength of the relationship between low HDL-C levels and increased CVD risk also is significant in elderly individuals and may be greater in women than in men.7,10,11 Angiographic and ultrasonographic data indicate that low levels of HDL-C are associated with risk and severity of coronary artery disease, carotid disease, and postangioplasty restenosis. Observational studies have shown that each 1 mg/dL decrease in plasma HDL-C concentration is associated with a 2% to 3% increased risk of CVD. Data from observational trials reveals that each 1 mg/dL increase in plasma HDL-C is associated with a 6% lower risk of coronary death, independent of LDL-C level. 11,12 However, this hypothesis has not been proven in an empowered clinical trial looking at CV outcomes, and although guidelines encourage elevation of HDL-C using lifestyle and FDA approved therapies, there is no specific HDL-C goal of therapy. The 2008 ADA/ACC consensus statement on treatment of patients with cardiometabolic risk advises normalization of apoB as the effective way to reduce risk in those with low HDL-C.13

Treatment Considerations

Agents That Modify HDL Composition

Nicotinic Acid (Niacin)

First recognized as a treatment for dyslipidemia in 1955, nicotinic acid can increase HDL-C levels by 20% to 30% as well as reduce plasma triglyceride levels by 40% to 50% and LDL-C levels by up to 20%.15-27 When tolerated, nicotinic acid represents the most effective HDL-C–increasing agent currently available. The most compelling data to support the use of niacin are from the Coronary Drug Project (CDP), which evaluated niacin monotherapy in 8341 men with prior myocardial infarction. In this prestatin study, niacin was associated with a 27% reduction in the incidence of nonfatal reinfarction at six years,15 and all-cause mortality was reduced by 11% at 15 years.21

Other clinical outcomes studies of niacin have been conducted in the setting of combination therapy, with bile acid sequestrants or statins, and thus the results should be interpreted in this context. In general, treatment with niacin, both as monotherapy and in combination with other antidyslipidemic agents, has produced consistent clinical and atherosclerotic burden benefit. The CVD benefit of niacin is difficult to judge as the drug lowers apoB, raises HDL-C, ApoA-I, and HDL-P and can lower Lp(a) as well as having many pleiotropic effects. The therapeutic potential of niacin has been limited by its adverse effects (flushing and pruritus), which can be reduced by use of an extended release formulation. The American Diabetes Association has cautioned against the use of niacin by patients with diabetes, although recent niacin studies have shown no significant increase in long-term glycemic levels, use of oral hyperglycemic regimens, or niacin withdrawal in these patients. Uric acid must be monitored and caution is need in patients with a history of gout or uric acid calculi.32,33

Statins

Statins modestly increase HDL-C levels by 5% to 15%, and this effect is most evident with rosuvastatin and pitavastin.3,34 However in the recent JUPITER trial where rosuvastatin reduced adverse events there was no rise in HDL-C.35 In fact, there is no statin outcome trial showing that event reduction was statistically related to the statin’s effect on HDL-C. The mechanism for statin-induced increase in HDL-C levels is presently unclear, although via a peroxisome proliferator-activated receptor (PPAR)-alpha effect, statins can increase levels of apoA-I and lipid-poor HDL. Statins have also been shown to reduce CETP activity and may also augment the activity of the antioxidant enzyme paraoxonase.36-39 In a recent post hoc analysis of 1,455 patients with low HDL-

C levels, statins reduced coronary atheroma independent of LDL-C when HDL-C levels were increased by at least 7.5%.40 However, while statins may confer a greater reduction in CVD among patients with lower HDL-C levels, independent of LDL-C effects, this may simply be due to the fact that those patients tend to have the highest apoB and LDL-P levels.41

Agents That Target Reverse Cholesterol Transport and Macrophage Cholesterol Efflux

Fibrates

Fibrates (gemfibrozil, fenofibrate) and their active fibric acid derivatives (gemfibric or fenofibric acid) are agonists of PPARα. These compounds can increase HDL-C levels (by 10%-20%), modestly lower LDL-C levels (by 10%- 15%), and substantially lower levels of triglycerides (by 40%-50%).28,29 They increase apoA-I, apoA-II and both total and small HDL species (the species most capable of lipidation by ABCA1). They upregulate ABCA1 and thus enhance HDL lipidation, but also upregulate hepatic SR-B1 which helps delipidate mature HDLs (converting them to smaller species). They inhibit CETP activity.

Several studies have elucidated the effect of fibrates on reverse cholesterol transport. In the Helsinki Heart Study and the VA-HIT trial, treatment with gemfibrozil was associated with reduction in CVD events.28,29 The 22% reduction in coronary events in the VA-HIT trial was attributed to a modest increase (6%) in HDL-C levels.29 In contrast, the results of studies using other fibrates such as bezafibrate and fenofibrate have been negative with respect to the primary outcomes (but, like niacin, positive for secondary outcomes), while clofibrate has been associated with potential hazard.15,28,34,37-42 Some evidence indicates that the benefits seen in the VA-HIT cohort may be partly due to additional effects of fibrates on apolipoprotein synthesis and lipoprotein metabolism.43,44 The combination of fibrates, particularly gemfibrozil, with statins requires caution and monitoring of creatine kinase levels because of the risk for myotoxicity, including rhabdomyolysis.45 Because of this safety concern and variable-outcome study results, the precise role of fibrate treatment remains uncertain but likely includes some patients at high risk of coronary artery disease, low levels of HDL-C, and increased levels of serum triglycerides.

Appropriate strategies to increase HDL-C levels (the majority of whom are insulin resistant, with high apoB and LDL-P levels) include aggressive overall lifestyle modification (exercise, diet, weight loss, and smoking cessation). Patients at increased risk for CHD with low HDL-C levels should be started on statins to get apoB and LDL-P to goal. Niacin and fenofibrate or fenofibric acid (if TG are > 200 mg/dL) therapy also merit consideration in combination with statin therapy in patients at high risk for CHD. Neither niacin nor a fibrate should be used as monotherapy in patients who are able to take a statin.

References

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