High density lipoprotein physiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ayokunle Olubaniyi, M.B,B.S [2]

Overview

The physiological role of HDL centers around the reverse cholesterol transport system. Nascent HDL secreted into the plasma by the liver or intestine pick up free cholesterol from peripheral tissues and the arterial wall, an action mediated mainly by the ATP-binding cassette A1 (ABCA1). The enzyme lecithin-cholesteryl acetyltransferase (LCAT) catalyzes the esterification of the free cholesterol, and also converts the nascent HDL into the mature form. The esterified cholesterol is transported to the liver where cholesterylester transfer protein (CETP), an enzyme produced in the liver, acts on it transferring the cholesterol to other apo B containing lipoproteins. The cholesterol-deplete HDL gets broken down by triglyceride lipases releasing apo A-I which either takes up free cholesterol to continue the cycle, or gets eliminated in the kidneys. In addition to its atheroprotective against cardiovascular diseases, HDL also exhibits anti-oxidant, anti-inflammatory, anti-apoptotic, anti-coagulant, vasodilatory, and metabolic properties.

Physiology

Structure

Lipoprotein Density Size % Protein Cholesterol in Plasma Triglyceride in Fasting Plasma Major Apolipoprotein
HDL 1.063 - 1.210 g/mL 6 - 10 mm 40 - 55% 0.9 - 1.6 mmol/L 0.1 - 0.2 mmol/L apoA-I, apoA-II

For more information about the biochemistry of all lipoproteins, click here.

Shown below is a schematic image depicting the structure of the HDL. Note that the inner core is made of triglyceride and cholesterol esters whereas the surface is made of amphiphilic phospholipids along with apolipoproteins.

The structure of the HDL: the inner core is made of triglyceride and cholesterol esters whereas the surface is  made of amphiphilic phospholipids along with apolipoproteins.

  • HDL is the smallest of the lipoproteins. It is the densest because it contains the highest proportion of protein. It contains the A class of apolipoproteins. Apolipoprotein A-I is the main protein of HDL that removes excess cell cholesterol and protects against atherosclerosis.[1]
  • The liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipids, which resemble cholesterol-free flattened spherical lipoprotein particles. They are capable of picking up cholesterol from cells they interact with.
  • A plasma enzyme called lecithin-cholesterol acyltransferase (LCAT) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol) which is then sequestered into the core of the lipoprotein particle eventually making the newly synthesized HDL spherical. They increase in size as they circulate through the bloodstream and incorporate more cholesterol molecules into their structure.
  • Thus it is the concentration of large HDL particles which more accurately reflects the HDL protective action, as opposed to the concentration of total HDL particles.[2] This ratio of large HDL to total HDL particles varies widely and is only measured by more sophisticated lipoprotein assays using either electrophoresis, originally developed in the 1970s, or newer nuclear magnetic resonance (NMR) spectroscopy which was developed in the 1990s.
  • HDL particles are not inherently protective. It is only the HDL particles which become the largest (actually picking up and carrying cholesterol) that are protective. There is no reliable relationship between total HDL and large HDL, and more sophisticated analyses which actually measure large HDL, and not just total HDL, correlate much better with clinical outcomes.[3]
  • Many studies have postulated an association between cholesterol efflux from peripheral tissue and Apo A-I HDL particles, whereas the HDL3 containing both Apo A-I and A-II are less effective.[4][5][6]

HDL Receptors

  • ABCA1 transporter: it is expressed in the peripheral tissues, intestine, liver, and macrophages.[7] An increase in intracellular cholesterol content upregulates ABCA1 transporter which is responsible for cholesterol efflux from the intracellular pool.[8]
  • ABCG1 transporter: it is expressed in the intestine and macrophages.[7] ABCG1 is also responsible for cholesterol efflux. In addition, ABCG1 may facilitate the oxidation of plasma membrane cholesterol domains.[9]

Enzymes Associated with HDL

Cholesterol Ester Transfer Protein (CETP)
  • CETP mediates exchange of cholesterol between HDL particles, and triglyceride rich LDL and VLDL in both directions.
  • CETP is normally present in both peripheral tissues and liver and functions to channel cholesterol to the liver for uptake and metabolism.
Lecithin-Cholesterol Acyltransferase (LCAT)
  • LCAT is an enzyme that catalyzes the transfer of fatty acyl chain to free cholesterol which results in cholesteryl ester formation.[14]
  • Its role in extracellular cholesterol metabolism may facilitate the uptake of cholesterol from peripheral tissues to liver into HDL particles by maintaining a concentration gradient for the efflux of free cholesterol which may play a major role in reverse cholesterol transport (RCT).[15]

Reverse Cholesterol Transport

HDL plays a pivotal role in cholesterol transport from peripheral tissues to the liver for excretion, a process known as reverse cholesterol transport. HDL’s protective atherosclerotic effect is related to its role in reverse cholesterol transport, where cholesterol efflux from macrophages to HDL is an important initial step.

Low concentration of HDL is one of the various risk factors of cardiovascular disease as demonstrated by preclinical and epidemiologic studies. Increasing HDL concentration by medical therapy, such as niacin and inhibition of cholesteryl ester transfer protein, was evaluated in many clinical trials. Studies such as ILLUMINATE,[16] dal-OUTCOMES,[17] and CHI-SQUARE, have failed to demonstrate an association between increasing HDL by therapy and improved cardiovascular outcomes. Higher cholesterol efflux capacity, however, is associated with a lower rate of cardiovascular disease, independently of HDL cholesterol concentration.[18] These findings highlight the importance of HDL function in reverse cholesterol transport and cholesterol efflux.

HDL-metabolism.gif

Adapted from Nature Reviews Drug Discovery. ABCA1= ATP-binding cassette transporter A1; ABCG1: ATP-binding cassette transporter G1; ABCG4: ATP-binding cassette transporter G4; ApoA-I= Apolipoprotein A-I; CETP: Cholesteryl transfer protein; LCAT: Lecithin cholesterol acyltransferase; SRBI: Scavenger receptor, class B, type I. [19]

Synthesis and Uptake of Cholesterol

  • HDL consists of phospholipids and apolipoproteins, mainly apo A-I and/or apo A-II. Both the liver and the small intestine synthesize apo A-I while only the liver synthesizes apo A-II.
  • Free apo A-I is released into the plasma as nascent HDLs. Nascent HDL readily takes up excess free cholesterol from the periphery such as fibroblasts, macrophages, and arterial wall, a process referred to as cholesterol efflux. This uptake of cholesterol is mediated by either ATP-binding cassette A1 (ABCA1), G1/G4, scavenger receptor class B type 1 (SR-B1), Cyp27A1, caveloin, and passive diffusion, leading to the formation of discoid HDL (a.k.a. pre-βHDL).
  • Apo A-I is a cofactor of lecithin-cholesterol acetyltransferase (LCAT) which catalyzes the esterification of the free cholesterol bound to the discoid HDL. The apolipoprotein A1 acts as a signal protein in mobilizing cholesteryl esters from within the cells.
Reverse cholesterol.jpg

Maturation and Transfer of Cholesterol

  • The esterified cholesterol moves into the hydrophobic core of the HDL, changing the HDL particle from discoid to spherical (mature HDL). This process also prevents the re-uptake of cholesterol by cells. LCAT is responsible for the maturation of HDL particles.
  • The esterified cholesterol can be delivered back to the liver through a number of routes:
    • CETP, secreted in the liver, transfers cholesterol from HDL to the apo B–containing lipoproteins e.g., very low-density lipoprotein (VLDL) or intermediate-density lipoprotein (IDL) to be taken up by the liver. Mutations of this transport protein gene causes familial HDL deficiencies and Tangier disease.
    • HDL particles may be taken up directly by the liver.
    • Free cholesterol may be taken up directly by the liver.
    • HDL cholesterol esters may be selectively taken up via the scavenger receptor SR-B1, which is expressed in the liver.

Catabolism

  • Triglyceride lipase degrades cholesterol-deplete HDL particles into small, dense HDL particles which release apo A-I (nascent HDL) after dissociation. The apo A-1 either rapidly re-uptakes free cholesterol again by ABCA1 to form discoid HDLs, or it is endocytosed into the kidney tubule, or cleared via glomerular filtration.

Role of HDL

Shown below is an image summarizing the physiologic functions of HDL in an acute and chronic setting. Please refer to the text below for details about each one of functions of HDL.

The physiologic functions of HDL in an acute and chronic setting

Atheroprotection

It has been established that HDL-cholesterol has an inverse correlation with future atherosclerotic cardiovascular complications. HDL and apo A-I exhibit many atheroprotective functions which primarily aim at removing cholesterol from peripheral tissues and the arterial wall through various efflux mechanisms, mainly the reverse cholesterol transport system. HDL also plays a role in the attenuation of plaque progression and promotion of plaque stabilization. These functions are exhibited through its anti-oxidative, anti-platelet, anti-apoptotic, and anti-inflammatory properties. With all these properties in context, HDL potentially protects against reperfusion ischemic injuries and secondary plaque rupture observed in post-acute coronary syndrome patients.

  • Plasma HDL associated apolipoprotein M (apoM) modulates the ability of plasma to mobilize cellular cholesterol and protects against experimental atherosclerosis.[20]
  • Animal models have demonstrated that the somatic gene transfer of human apo A-I can prevent the development of atherosclerosis or reverse preexisting atherosclerosis.[21][22][23][24]
  • ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 in endothelial cells and the scavenger receptor B type I mediate multiple intracellular signaling pathways as well as the efflux of cholesterol.[25]

Anti-Coagulation Function

HDL has the ability to inhibit platelet activation and aggregation by directly inhibiting platelet activation,[26][27] downregulating thromboxane A2 synthesis,[28] increasing the synthesis of prostacyclin,[29] and lowering the expression of the tissue factor which is required in the coagulation process.[30]

Anti-Oxidant Function

The formation of free oxygen radicals contributes to the pathogenesis and progression of atherosclerotic plaques. Oxidized LDL is engulfed by macrophages, which leads to further oxidation and production of foam cells. Oxidized LDL acts as a chemotactic agent for circulating monocytes, converts macrophages into foam cells, induces cytotoxic effects on the endothelium, inhibits motility of tissue macrophages, and stimulates the migration and proliferation of vascular smooth muscle cells.[31] HDL also inhibits the oxidative modification of oxidized LDLs,[32] and prevents their infiltration into the vessel wall.[33]

Anti-Inflammatory Function

HDL has anti-inflammatory functions in both endothelial cells and leukocytes. During inflammation, several leukocyte adhesion molecules are activated, which promotes the binding of leukocytes and formation of atheroma. HDL inhibits the activation of vascular cell adhesion molecule (VCAM-1),[34] interleukin-1-induced expresion of E-selectin,[35] interleukin-8, intracellular adhesion molecule (ICAM)-1, neutrophils,[36] monocytes,[37] and also prevents the binding of T-lymphocytes to monocytes thereby preventing the formation of pro-inflammatory cytokines.[38]

Metabolic Function

In a study on the effects and mechanisms of HDL on glucose metabolism, 13 type 2 diabetes patients were administered intravenous reconstituted HDL. There was a reduction in the plasma glucose of the patients due to an increase in plasma insulin in addition to the activation of AMP-activated protein kinase in the skeletal muscle. These findings suggest a role for HDL-raising therapies beyond atherosclerosis to address type 2 diabetes mellitus.[39]

Glucose Metabolism

HDL might modulate glucose homeostasis through several mechanisms such as the stimulation of insulin secretion,[40][41][39][42] enhancement of insulin sensitivity, and increased glucose uptake by skeletal muscle via activation of AMP-activated protein kinase (AMPK) signaling pathway.[43][41] Preliminary evidence from genetic engineering studies that manipulate expression of related genes such as ABCA1,[44][45][46][47] CETP,[48][49] ABCG1,[50] and apoA-I[43] suggests associations between plasma HDL concentrations and glycemic control. Silencing of microRNA species was also been associated with upregulation of these target genes along with elevation of functional HDL levels,[51][52][53][54] suggesting an extensively-linked yet fine-tuned state of homeostasis in energy metabolism.

Diabetes Mellitus

Type 2 diabetes mellitus and impaired fasting glucose are both associated with decreased levels of HDL.[55][56] In the Framingham Offspring Study, low levels of HDL cholesterol was reported as a significant predictor of incident type 2 diabetes mellitus.[57]

Anti-Apoptotic Function

Plasma HDL offers some cytoprotection against oxidized LDL-mediated apoptosis and generation of reactive oxygen species in-vitro .[58] HDL also protects endothelial cells from apoptosis and promotes their growth and their migration via SRBI-initiated signaling.[59] It is also suggested that the anti-apoptotic and proliferative effects of apoA-I are mediated through F1-ATPase-catalysed ADP production and subsequent P2Y13 receptor stimulation.[60]

Vasodilatory Function

HDL might play a role in the restoration of endothelial dysfunction implicated in the pathogenesis of type 2 diabetes. In one study, reconstituted HDL was infused in patients with type 2 diabetes and the vascular function (forearm blood flow) was assessed at 4 hours and 7 days post-infusion. HDL infusion was associated with an increase in the forearm blood flow in diabetic patients as compared to the controlled group, probably due to its effect on increasing the bioavailability of nitric oxide.[61]

References

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