HDL Receptors

Atherosclerosis is a leading cause of cardiovascular disease, contributing to deaths worldwide. However, high-density lipoprotein (HDL) has a protective effect. Indeed, atherosclerosis is inversely related to plasma levels of high-density lipoprotein (HDL) cholesterol.

Specifically, HDL performs an important role in reverse cholesterol transport by removing accumulated cholesterol from extrahepatic tissues. Receptors enhance the flux of unesterified or free cholesterol. Scavenger receptors are cell-surface transmembrane proteins that can bind modified lipoproteins. Cell surface receptors for HDL on liver cells (hepatocytes) are major partners in the regulation of cholesterol homeostasis. The scavenger receptor class B type I (SR-BI) has been identified as a functional HDL binding protein. Nonetheless, the molecular mechanism by which the receptor mediates selective cholesteryl ester uptake still needs to be explored

[Page 347]SR-BI is abundantly expressed in several tissues, including the liver, where its expression is regulated by various mechanisms. SR-BI mediates both the selective uptake of lipids, mainly cholesterol esters, from HDL to cells and the efflux of cholesterol from cells to lipoproteins in liver and steroidogenic tissues. In addition to mediating selective lipid uptake from lipoproteins to cells, SR-BI can mediate the bidirectional movement of unesterified cholesterol between lipoproteins and cells. The binding of HDL to SR-BI mediates cholesterol movement bi-directionally, down a concentration gradient, the extent of which seems to depend on the cholesterol concentration gradient between HDL particles and the plasma membrane. The constitutive expression of SR-BI alters the steady state level of cellular cholesterol and phospholipid. However, the effects are proportional to the level of receptor on the cell surface. The level of SR-BI expression determines both the rate of free cholesterol flux and the steady state level of cellular cholesterol.

HDLs consist of a variety of particles with different sizes, densities, and lipid and protein compositions. The most abundant protein component of HDL is apolipoprotein A-I (apoA-I). Differences in apoA-I conformation in different-sized particles notably influence apoA-I recognition by SR-BI. Indeed, the preferential binding of larger HDL particles to SR-BI promotes selective cholesteryl ester uptake from larger cholesteryl ester-rich HDL over lipid-poor HDL. Particularly, the larger, cholesteryl ester–rich, lower density, spherical-HDL particles bind more tightly to SR-BI than higher density HDLs, lipid-poor pre-ß-HDL or lipid-free apoA-I. The ability of SR-BI to bind a wide variety of lipoprotein classes suggests that the conformation of apoA-I in HDL particles is important for the formation of a productive HDL/SR-BI interaction. The relative contents of apoA-I and apoA-II in spherical HDL particles may also affect their interactions with SR-BI.

The scavenger receptor class B type I (SR-BI) was the first molecularly well-defined cell-surface HDL receptor to be described. SR-BI mediates selective HDL cholesterol uptake by formation of a lipoprotein/receptor complex, which requires specific structural domains and conformation states of apolipoprotein A-I which is present in HDL particles. HDL signaling requires cholesterol binding and efflux and SR-BI serves as a cholesterol sensor on the plasma membrane. Hepatic SR-BI expression can be regulated by a variety of dietary, hormonal, metabolic, and pharmacological manipulations.