[5] The receptors can be recycled, whereas the lipoprotein remnants in the vesicle are transferred to lysosomes and degraded by lysosomal acid hydrolases, releasing free cholesterol, amino acids, FA, and phospholipids. These compounds can be reutilized by the cell. [Note: Lysosomal storage diseases result from rare autosomal-recessive deficiencies in the ability to hydrolyze lysosomal cholesteryl esters (Wolman disease) or to transport free cholesterol out of the lysosome (Niemann-Pick disease, type C).] 2. Endocytosed cholesterol and cholesterol homeostasis: The chylomicron remnant–, IDL-, and LDL-derived cholesterol affects cellular cholesterol content in several ways (see Fig. 18.20). First, expression of the gene for HMG CoA reductase is inhibited by high cholesterol, and de novo cholesterol synthesis decreases as a result. Additionally, degradation of the reductase is accelerated. Second, synthesis of new LDL receptor protein is reduced by decreasing the expression of the LDL receptor gene, thus limiting further entry of LDL-C into cells. [Note: As was seen with the reductase gene (see p. 222), transcriptional regulation of the LDL receptor gene involves an SRE and SREBP-2. This allows coordinate regulation of the expression of these proteins.] Third, if the cholesterol is not required immediately for some structural or synthetic purpose, it is esterified by acyl CoA:cholesterol acyltransferase (ACAT). ACAT transfers a FA from a fatty acyl CoA to cholesterol, producing a cholesteryl ester that can be stored in the cell (Fig. 18.21). The activity of ACAT is enhanced in the presence of increased intracellular cholesterol.
3. Uptake by macrophage scavenger receptors: In addition to the highly specific and regulated receptor-mediated pathway for LDL uptake described above, macrophages possess high levels of scavenger receptor activity. These receptors, known as scavenger receptor class A (SR-A), can bind a broad range of ligands and mediate the endocytosis of chemically modified LDL in which the lipid or apo B component has been oxidized. Unlike the LDL receptor, the scavenger receptor is not downregulated in response to increased intracellular cholesterol. Cholesteryl esters accumulate in macrophages and cause their transformation into “foam” cells, which participate in the formation of atherosclerotic plaque (Fig. 18.22). LDL-C is the primary cause of atherosclerosis.
E. 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 perform 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.