Biosynthesis and Catabolism of Lipoproteins Containing Apo B
Apo B, in concert with microsomal triglyceride transfer protein (MTP), is required for the assembly of chylomicrons and VLDL in the ER of enterocytes and hepatocytes, respectively. The nascent lipoproteins are transported to the Golgi apparatus, packaged in secretory vesicles, and delivered into the extracellular space by exocytosis (see Chap. 115). Chylomicrons enter lacteals in the intestinal villi, and VLDL pass through the fenestrae of the hepatic sinusoidal endothelium to enter the blood.
Nascent chylomicrons contain newly absorbed fatty acids as triglycerides. Their protein components include the smaller form of apo B (B-48) and the A apoproteins (A-I, A-II, and A-IV) (Fig. 114-1). After secretion, chylomicrons acquire C apoproteins and apo E by transfer from HDL. Following delivery via the thoracic duct into the blood, chylomicrons bind to lipoprotein lipase on the surface of capillary endothelial cells, where most of the triglycerides are rapidly hydrolyzed together with some of the surface glycerophospholipids. Concomitantly, some phospholipids and the A apoproteins are transferred to HDL. With these changes, the particles gradually lose their affinity for C apoproteins, which are also transferred to HDL; the residual particle, now called a “chylomicron remnant,” is released into the blood. The remnant binds to proteins located on the sinusoidal surface of hepatocytes, chiefly the LDL receptor and hepatic lipase. Hepatic lipase further hydrolyzes remnant lipids, and the particles may acquire additional apo E, which is bound, like hepatic lipase, to heparan sulfate proteoglycans on the cell surface. Such modifications are not required for effective binding of remnants to the LDL receptor, but facilitate binding to a second receptor (LRP). After endocytosis via coated pits, components of the particle are hydrolyzed in lysosomes.
Chylomicron pathway. Dietary triglycerides are hydrolyzed in the intestine by pancreatic lipase to fatty acids (FFA) and monoglycerides (MG), which are reesterified to form triglycerides (TG) in intestinal mucosal cells. Dietary cholesterol is likewise esterfied with long chain fatty acids in the mucosal cells to form cholesteryl esters. The triglycerides and cholesteryl esters are assembled in the ER with other lipids and proteins to form the core of nascent chylomicrons. Apo B-48, acting in concert with microsomal triglyceride transfer protein (MTP), is required for chylomicron particle assembly, which is completed in the Golgi apparatus. After secretion into intestinal lymph, the nascent chylomicrons are delivered into the blood, where the proteins synthesized in the absorptive cells (apo B-48 and the A apoproteins) are augmented by transfer of apo E and C apoproteins from HDL. The first step in chylomicron catabolism occurs in extrahepatic tissues, where most of the component triglycerides (shaded area in particles) are rapidly hydrolyzed by lipoprotein lipase to yield chylomicron remnants (see text). The remnants, which retain their component cholesteryl esters (black area in particles) are released from the enzyme and are then taken up onto the surface of hepatocytes by the LDL receptor and hepatic lipase. Hepatic lipase-bound remnants may be further processed enzymatically and may acquire additional apo E residing on the cell surface. The LDL receptor and the LDL receptor-related protein (LRP) bind remnants via apo E, leading to endocytosis of the particles and catabolism in lysosomes from which cholesterol can enter metabolic pathways in hepatocytes, including excretion into the bile. (Modified from Havel RJ.15 Used with the permission of the publisher.)
During the first step of chylomicron metabolism in extrahepatic tissues, most of the triglyceride fatty acids enter adipocytes for storage or cells of other tissues for oxidation. In addition, some of the released fatty acids become bound to plasma albumin and are transported to a variety of tissues, including the liver. During the second step of chylomicron metabolism, the residual triglycerides, and virtually all dietary cholesterol, are delivered to hepatocytes. The cholesterol released from lysosomes in hepatocytes can enter pathways leading to the formation of bile acids, be secreted into the bile as such, be incorporated into nascent lipoproteins, or be esterified with a long chain fatty acid and stored in lipid droplets within the cell.
VLDL provide a pathway for export from hepatocytes of excess triglycerides (derived from lipogenesis, from plasma free fatty acids, or from chylomicron remnants taken up from the blood), which would otherwise be stored within the cells. As they enter the blood, nascent VLDL contain the larger form of apo B (B-100) and small amounts of E and C apoproteins (Fig. 114-2). Additional amounts of the latter proteins are added after secretion, as in the case of nascent chylomicrons. Thereafter, the initial phase of metabolism resembles that of chylomicrons—hydrolysis by lipoprotein lipase and the formation of VLDL remnants. The rate of hydrolysis of VLDL triglycerides is slower than that of chylomicron triglycerides. This is probably related to the smaller size of the average VLDL particle, which can bind fewer lipoprotein lipase molecules than the larger chylomicron particle. The normal residence time for chylomicron triglycerides in the blood is 5 to 10 min, whereas for VLDL triglycerides it is l5 to 60 min.
VLDL-LDL pathways. The formation of VLDL in hepatocytes resembles that of chylomicrons in intestinal absorptive cells. VLDL provide a pathway for exit of surplus fatty acids as triglycerides (shaded area in lipoprotein particles) from the liver (see text). VLDL also transport cholesteryl esters from the liver (black areas), but most of these esters are synthesized by LCAT in species of HDL and transferred to the VLDL particles in the blood. The liver synthesizes a larger form of apo B (B-100) than the B-48 protein synthesized in the intestine, and also synthesizes apo E and C apoproteins, which enter the blood with nascent VLDL. As with chylomicrons, most VLDL triglycerides are hydrolyzed in extrahepatic tissues by lipoprotein lipase to yield remnant particles. LDL receptors on hepatocytes recognize apo E on VLDL remnants and mediate the endocytosis of a substantial fraction of these particles. Some, however, are further processed by hepatic lipase, also located on the hepatocyte surface, to yield LDL. LDL can also be taken up into hepatocytes by LDL receptors (which recognize a binding domain on apo B-100) or by LDL receptors on extrahepatic cells. Unlike their remnant precursors, which have a short life span, LDL circulate in the blood for days (see text). (Modified from Havel RJ.15 Used with the permission of the publisher.)
VLDL remnants can interact with LDL receptors on hepatocytes via apo E. The presence of several molecules of apo E on larger remnant particles results in high-affinity binding and rapid removal of the remnants from the blood followed by lysosomal catabolism. Smaller VLDL particles yield smaller remnants, with fewer molecules of apo E; these have lower affinity for hepatic LDL receptors and remain longer in the blood. The smaller remnants include particles that are isolated as IDL. Many of these particles are further lipolyzed after binding to hepatic lipase on the hepatocyte surface to form LDL. LDL contain little or no apo E, but can bind to the LDL receptor monovalently via component apo B-100.
Although nascent VLDL contain apo E, the binding domain is not initially exposed for interaction with LDL receptors. During the formation of VLDL remnants, and particularly with the loss of C apoproteins, the binding domain becomes exposed, permitting uptake by LDL receptors. Similarly, the binding domain of apo B is not exposed in nascent VLDL, but eventually becomes exposed during lipolysis, so that as apo E is lost, the particle retains some affinity for the LDL receptor. The relatively low affinity of LDL for the LDL receptor, as compared with that of VLDL remnants, presumably accounts for the long residence time of LDL particles (about 3 days), as compared with that of VLDL remnants (minutes to hours).
The endocytosis of chylomicron remnants into hepatocytes is also mediated by apo E and, as with nascent VLDL, exposure of the binding domain of apo E requires lipolysis, accompanied by loss of C apoproteins. In contrast to VLDL, particles equivalent to LDL are not formed during the lipolysis of chylomicron remnants. In addition, the B-48 protein of chylomicrons lacks the receptor-binding domain present in apo B-100, and consequently is thought not to participate in remnant uptake into the liver (see Chap. 120).
In most mammals, VLDL remnants are taken up mainly into the liver and only a small fraction is converted to LDL. In humans, more remnants, perhaps about half, are eventually converted to LDL. Whereas remnants are taken up almost entirely into the liver, some LDL particles are taken up into extrahepatic tissues, mainly via the LDL receptor. Normally, the liver is also the principal site of removal of LDL from the blood. In general, the higher the activity of LDL receptors on hepatocytes, the greater the efficiency of removal of VLDL remnants and the lower the fraction of remnants converted to LDL (see Chap. 120).