Lecithinxholesterol acyltransferase

Figure 25-5. Metabolism of high-density lipoprotein (HDL) in reverse cholesteroi transport. (LCAT, lecithinxholesterol acyltransferase C, cholesterol CE, cholesteryl ester PL, phospholipid A-l, apolipoprotein A-l SR-Bl, scavenger receptor B1 ABC-1, ATP binding cassette transporter 1.) Prep-HDL, HDLj, HDL3—see Table 25-1. Surplus surface constituents from the action of lipoprotein lipase on chylomicrons and VLDL are another source of preP-HDL. Hepatic lipase activity is increased by androgens and decreased by estrogens, which may account for higher concentrations of plasma HDLj in women.

Fig. 5.2.1 The major metabolic pathways of the lipoprotein metabolism are shown. Chylomicrons (Chylo) are secreted from the intestine and are metabolized by lipoprotein lipase (LPL) before the remnants are taken up by the liver. The liver secretes very-low-density lipoproteins (VLDL) to distribute lipids to the periphery. These VLDL are hydrolyzed by LPL and hepatic lipase (HL) to result in intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), respectively, which then is cleared from the blood by the LDL receptor (LDLR). The liver and the intestine secrete apolipoprotein AI, which forms pre-jS-high-density lipoproteins (pre-jl-HDL) in blood. These pre-/ -HDL accept phospholipids and cholesterol from hepatic and peripheral cells through the activity of the ATP binding cassette transporter Al. Subsequent cholesterol esterification by lecithinxholesterol acyltransferase (LCAT) and transfer of phospholipids by phospholipid transfer protein (PLTP) transform the nascent discoidal high-density lipoproteins (HDL disc) into a spherical particle and increase the size to HDL2. For the elimination of cholesterol from HDL, two possible pathways exist (1) direct hepatic uptake of lipids through scavenger receptor B1 (SR-BI) and HL, and (2) cholesteryl ester transfer protein (CfiTP)-mediated transfer of cholesterol-esters from HDL2 to chylomicrons, and VLDL and hepatic uptake of the lipids via the LDLR pathway...

Figure 15-2. A simplified schematic of cholesterol transport. Cholesterol travels to non-hepatic cells, such as the macrophage, via VLDL and LDL particles, while excess cholesterol is shuttled to the liver via HDL particles. Note that AHCAl mediates nascent HDL formation by translocating cellular cholesterol and phospholipids to apolipoprotein A-I (apoA-I) in an active, energy-dependent reaction. CETP, cholesteryl ester transfer protein LCAT, lecithinxholesterol acyltransferase LDLR, low-density lipoprotein receptor SR-B1, scavenger receptor Bl.

Apo-A-1 Chylomicrons, HDL Major protein of HDL, activates lecithinxholesterol acyltransferase, LCAT... 

Apo A-I, which consists of 243 amino acids, is the major protein of the HDLs (Schmidt et ah, 1995). Apo A-I accoimts for about 70% of the protein in the HDL. This protein serves as a cofactor for lecithinxholesterol acyltransferase (LCAT), and also to facilitate the binding of HDLs to plasma membranes, and to facilitate the removal of cholesterol from tissues. A number of genetic mutations in apo A-I have been discovered. Where the genetic mutation results in the complete absence of apo A-I, the result is atherosclerosis and xanthomas. For example, one patient s mutated apo A-I was truncated and consisted of only the first 84 amino acids, of the normal 243 amino acid polypeptide (Matsunaga et al, 1991). 

FIGURE 21-2. Overview of lipoprotein metabolism. (ACAT = acyl CoAxholesterol acyltransferase CETP = cholesteryl ester transfer protein FA = fatty acid FFA = free fatty acid HMGR = HMG CoA reductase LCAT = lecithinxholesterol acyltransferase PAP = phosphatidic acid phosphatase). (From Ref. 17 with permission.)... 

Apo Al, like apo B, is secreted mainly from liver and intestinal cells. Unlike apo B, however, apo Al is secreted in lipid-free or lipid-poor from. The cholesterol and phospholipids that are transferred to HDLs move down concentration gradients driven by the plasma enzyme lecithinxholesterol acyltransferase (LCAT). LCAT, which is bound to HDL, converts cholesterol and phosphatidylcholine to insoluble CE and lysophos-phatidylcholine (Section 3.4), which is soluble and is transferred to albumin in the plasma. Cholesterol has a small but significant solubility and, as a result, can be transferred spontaneously from cell and lipoprotein surfaces to apo Al. Cholesterol may also be transferred as a result of molecular collision between lipoprotein particles. The LCAT reaction consumes equal amounts of cholesterol and phospholipids, but the rate at which phospholipids are transferred spontaneously between cells and lipoproteins is much lower... 

Fig. 7. A model illustrating how pre-beta,-HDL, reacting directly with lecithinxholesterol acyltransferase (LCAT), may fuse to generate spherical HDLs containing multiple apo A1 subunits. Based on experimental data in Ref. [15].

Fig. 1. Simplified schematic summary of the essential pathways for receptor-mediated human lipoprotein metabolism. The liver is the crossing point between the exogenous pathway (left-hand side), which deals with dietary lipids, and the endogenous pathway (right-hand side) that starts with the hepatic synthesis of VLDL. The endogenous metabolic branch starts with the production of chylomicrons (CM) in the intestine, which are converted to chylomicron remnants (CMR). Very-low-density lipoprotein particles (VLDL) are lipolyzed to LDL particles, which bind to the LDL receptor. IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, high-density lipoproteins LCAT, lecithinxholesterol acyltransferase CETP, cholesteryl ester transfer protein A, LDL receptor-related protein (LRPl) and W, LDL receptor. Lipolysis denotes lipoprotein lipase-catalyzed triacylglycerol lipolysis in the capillary bed.

In addition, cholesterol accumulation in macrophages, mediated by modified lipoproteins (e. g., acetylated low-density lipoprotein, AcLDL), stimulates these cells to synthesize and secrete apolipoprotein (Apo) E/phospholipid discs. During the intraplasmatic cholesterol esterification process mediated by lecithinxholesterol acyltransferase (LCAT), HDL are assumed to incorporate unesterified cholesterol from the cell surface and Apo E from secreted Apo E/phospholipid discs and thereby mediate reverse cholesterol transport from peripheral cells back to the liver. The resulting cholesteryl ester- and Apo E-enriched HDLi are transported to the liver where they may be recognized by a hepatic Apo E receptor. 

Decreased Apo A1 appears to be a major component of the dyslipi-demic serum profile in patients with atherosclerotic occlusive disease of the lower extremities (461). Despite similar TC and HDL-C levels, A1 HDL is more anti-atherogenic than A1/A2 HDL in transgenic mice (462). This is because lecithinxholesterol acyltransferase (LCAT) and cholesteryl ester trasfer protein (CETP) are present mainly in Lp A1 and because Lp A1 A2 can inhibit Lp A1 -promoted cholesterol efflux. Also, mice overexpressing Apo A1 have more cholesterol efflux and are more protected against atherosclerosis mediated through decreased foam cell... 

---