Fig. 7.1 ). The first step in the synthesis is the secretion of triglyceride-rich very-low-density lipoprotein (VLDL) by the liver into the blood. In the capillaries of adipose tissue and muscle, the VLDL particle undergoes lipolysis and is converted to intermediate-density lipoprotein (IDL). In comparison with VLDL, the content of triglyceride is reduced and that of cholesteryl esters is enriched in IDL, but IDL retains on its surface the VLDL-associated apolipoproteins B-100 and E. Further metabolism of IDL occurs along two pathways: Most of the http://ebooksmedicine.net
Fig. 7.1 Low-densitylipoprotein(LDL)metabolismandtheroleoftheliverinitssynthesisandclearance.Lipolysisofvery-low-densitylipoprotein(VLDL)bylipoproteinlipaseinthecapillariesreleasestriglycerides,whicharethenstoredinfatcellsandusedasasourceofenergyinskeletalmuscles.IDL(intermediate-densitylipoprotein)remainsinthebloodandistakenupbytheliver.
IDL particles are directly taken up by the liver through the LDL receptor described later; others are converted to cholesterol-rich LDL by a further loss of triglycerides and the loss of apolipoprotein E. In the liver cells, IDL is recycled to generate VLDL.
The LDL receptor pathway metabolizes two-thirds of the resultant LDL particles, and the rest is metabolized by a receptor for oxidized LDL (scavenger receptor), to be described later. The LDL receptor binds to apolipoproteins B-100 and E and thus is involved in the transport of both LDL and IDL. Although the LDL receptors are widely distributed, approximately 75% are located on hepatocytes, so the liver plays an extremely important role in LDL metabolism. The first step in the receptor-mediated transport of LDL involves binding to the cell surface receptor, followed by endocytotic internalization inside so-called clathrin-coated pits (Fig. 7.2 ). Within the cell, the endocytic vesicles fuse with the lysosomes, and the LDL molecule is enzymatically degraded, resulting ultimately in the release of free cholesterol into the cytoplasm. The exit of cholesterol from the lysosomes requires the action of two proteins, called NPC1 and NPC2 (described later). The cholesterol not only is used by the cell for membrane synthesis but also takes part in intracellular cholesterol homeostasis by a sophisticated system of feedback control:
It suppresses cholesterol synthesis by inhibiting the activity of the enzyme 3-hydroxy-3-methylglutaryl– coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in the synthetic pathway.
It stimulates the formation of cholesterol esters for storage of excess cholesterol.
It downregulates the synthesis of cell surface LDL receptors, thus preventing excessive accumulation of cholesterol inside cells.
The transport of LDL by the scavenger receptors, alluded to earlier, seems to occur in cells of the mononuclear-phagocyte system and possibly in other cells as well. Monocytes and macrophages have receptors for chemically modified (e.g., acetylated or oxidized) LDLs. The amount catabolized by this scavenger receptor pathway is directly related to the plasma cholesterol level.