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 nonhepatic (peripheral) tissues and return it to the liver as cholesteryl esters (Fig. 18.23). [Note: HDL particles are excellent acceptors of nonesterified cholesterol as a result of their high concentration of phospholipids, which are important solubilizers of cholesterol.] 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. 18.23). CETP (see p. 231) 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 (see p. 231).
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, steroidogenic 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 (see p. 232 for SR-A receptors). 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.]