High-density lipoprotein metabolism

HDL comprise a heterogeneous family of lipoproteins with a complex metabolism that is not yet completely understood. HDL particles are formed in the blood by the addition of lipid to apo A-1, an apolipoprotein made and secreted by the liver and intestine. Apo A-1 accounts for ~70% of the apolipoproteins in HDL. HDL performs a number of important functions, including the following.

1. Apolipoprotein supply: HDL particles serve as a circulating reservoir of apo C-II (the apolipoprotein that is transferred to VLDL and chylomicrons and is an activator of LPL) and apo E (the apolipoprotein

required for the receptor-mediated endocytosis of IDL and chylomicron

remnants).

2. Nonesterified cholesterol uptake: Nascent HDL are disc-shaped particles containing primarily phospholipid (largely PC) and apo A, C, and E.

They take up cholesterol from non-hepatic (peripheral) tissues and return

it to the liver as cholesteryl esters (Fig. 1). [Note: HDL particles are excellent acceptors of nonesterified cholesterol as a result of their high concentration of phospholipids, which are important solubilizers of cholesterol.]

Figure 1: Metabolism of high-density lipoprotein (HDL) particles. Apo = apolipoprotein; ABCA1 = ATP-binding cassette transport protein; C = cholesterol; CE = cholesteryl ester; LCAT = lecithin:cholesterol acyltransferase; VLDL, IDL, and LDL = very-low-, intermediate-, and low-density lipoproteins; CETP = cholesteryl ester transfer protein; SR-B1 = scavenger receptor B1.

3. Cholesterol esterification: The cholesterol taken up by HDL is immediately esterified by the plasma enzyme lecithin:cholesterol acyltransferase (LCAT, also known as PCAT, in which P stands for phosphatidylcholine, the source of the FA). This enzyme is synthesized and secreted by the liver. LCAT binds to nascent HDL and is activated by apo A-I. LCAT transfers the FA from carbon 2 of PC to cholesterol.

This produces a hydrophobic cholesteryl ester, which is sequestered in the core of the HDL, and lysophosphatidylcholine, which binds to albumin. [Note: Esterification maintains the cholesterol concentration gradient, allowing continued efflux of cholesterol to HDL.] As the discoidal nascent HDL accumulates cholesteryl esters, it first becomes a spherical, relatively cholesteryl ester–poor HDL3 and, eventually, a cholesteryl ester–rich HDL2 particle that carries these esters to the liver.

Hepatic lipase, which degrades TAG and phospholipids, participates in the conversion of HDL2 to HDL3 (see Fig. 1). CETP   transfers some of the cholesteryl esters from HDL to VLDL in exchange for TAG, relieving product inhibition of LCAT. Because VLDL are catabolized to LDL, the cholesteryl esters transferred by CETP are ultimately taken up by the liver.

4. Reverse cholesterol transport: The selective transfer of cholesterol from peripheral cells to HDL and from HDL to the liver for bile acid synthesis or disposal via the bile is a key component of cholesterol homeostasis.

This process of reverse cholesterol transport (RCT) is, in part, the basis for the inverse relationship seen between plasma HDL concentration and

atherosclerosis and for the designation of HDL as the “good” cholesterol

carrier. [Note: Exercise and estrogen raise HDL levels.] RCT involves efflux of cholesterol from peripheral cells to HDL, esterification of the cholesterol by LCAT, binding of the cholesteryl ester–rich HDL (HDL2)

to liver (and, perhaps, steroid genic cells), selective transfer of the cholesteryl esters into these cells, and release of lipid-depleted HDL  (HDL3). The efflux of cholesterol from peripheral cells is mediated primarily by the transport protein ABCA1. [Note: Tangier disease is a very rare deficiency of ABCA1 and is characterized by the virtual absence of HDL particles due to degradation of lipid-poor apo A-1.]

Cholesteryl ester uptake by the liver is mediated by the cell-surface receptor SR-B1 (scavenger receptor class B type 1) that binds HDL . The HDL particle itself is not taken up.

Instead, there is selective uptake of the cholesteryl ester from the HDL particle. [Note: Low HDL-C is a risk factor for atherosclerosis.]  ABCA1 is an ATP-binding cassette (ABC) protein. ABC proteins use energy from ATP hydrolysis to transport materials, including lipids, in and out of cells and across intracellular compartments. In addition to Tangier disease, defects in specific ABC proteins result in sitosterolemia, cystic fibrosis, X-linked adrenoleukodystrophy, respiratory distress syndrome due to decreased surfactant secretion, and liver disease due to decreased bile salt secretion.