Lipoproteins Are Made in the ER Exported by the Secretory Pathway and Remodeled in the Circulation

Only two types of lipoproteins, VLDL and chylomicrons, are fully formed within cells by assembly in the ER, a process that requires the activity of microsomal transfer protein. The assembled particles move through the secretory pathway to the cell surface and are released by exocytosis—VLDL from liver cells and chylomicrons from intestinal epithelial cells (see Figure 18-10b). LDLs, IDLs (intermediate-density lipoproteins), and some HDLs are generated extracellularly in the bloodstream and on the surfaces of cells by the remodeling of secreted VLDLs and chylomicrons. There are four types of modifications:

■ Hydrolysis of triglycerides and phospholipids by lipases and esterification of cholesterol by an acyl transferase

■ Transfer of cholesteryl esters, triglycerides, and phospho-lipids between lipoproteins by specific lipid-transfer proteins

■ Uptake by some particles of cholesterol and phospholipids exported from cells

■ Association and dissociation of some apolipoproteins from the surfaces of the particles

For example, VLDL secreted from hepatocytes is converted into IDL and eventually into LDL, which can then deliver its cholesterol to cells through LDL receptors (Figure 18-13a). Similarly, chylomicrons carrying dietary lipids from the intestines are converted by lipase hydrolysis into chy-lomicron remnants, which eventually undergo endocytic uptake by the liver (Figure 18-13b). Small pre^-HDL particles are generated extracellularly from apoA apolipoproteins, secreted mainly by liver and intestinal cells, and from small amounts of cholesterol and phospholipid. They are then further converted into larger, spherical HDL particles, which constitute the bulk of the HDL found in the blood (Figure 18-13c). A major way that pre^-HDL particles grow larger is by accepting phospholipids and cholesterol exported from cells with the aid of yet another ABC protein called ABCA1 (see Table 18-2). This protein was implicated in the formation of HDL when defects in the ABCA1 gene were shown to cause Tangier's disease, a very rare genetic disease in which affected persons have almost no HDL in their blood. After being incorporated into HDL, cholesterol is esterified by lecithin:cholesterol acyl transferase (LCAT), an enzyme present in the plasma. Large HDL particles can transfer their cholesteryl esters to other lipoproteins through cholesteryl ester-transfer protein (CETP) or to cells (especially the liver and steroidogenic cells) through the receptor SR-BI, discussed later.

Capillaries

(b) Dietary lipids

Intestinal cell li

Remnant

Remnant receptors (LDLR/LRP)

Remnant receptors (LDLR/LRP)

Capillaries

Capillaries

Lipoprotein lipase

Capillaries

Lipoprotein lipase

ApoA

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