VLDL particles

PPAR5 Ubiquitous Potent TG- and LDL-C-lowering and potent HDL-C-raising increased oxidative disposal of fatty acids in adipose and skeletal muscle thermogenesis weight loss Fatty acids, eicosanoids (fatty acids derived from VLDL particles ) GW501516 currently in Phase II clinical trials Dyslipidemia, obesity atherosclerosis ... 

VLDL is the precursor of IDL, which is then converted to LDL. Only one molecule of apo B-lOO is present in each of these lipoprotein particles, and this is conserved during the transformations. Thus, each LDL particle is derived from only one VLDL particle (Figure 25-4). Two possible fates await IDL. It can be taken up by the liver directly via the LDL (apo B-lOO, E) receptor, or it is converted to LDL. In humans, a relatively large proportion forms LDL, accounting for the increased concentrations of LDL in humans compared with many other mammals. 

The reason for the cholesterol-lowering effect of polyunsaturated fatty acids is still not fully understood. It is clear, however, that one of the mechanisms involved is the up-regulation of LDL receptors by poly-and monounsaturated as compared with saturated fatty acids, causing an increase in the catabolic rate of LDL, the main atherogenic lipoprotein. In addition, saturated fatty acids cause the formation of smaller VLDL particles that contain relatively more cholesterol, and they are utilized by extrahepatic tissues at a slower rate than are larger particles—tendencies that may be regarded as atherogenic. 

Both intact carotenoids and their apolar metabolites (retinyl esters) are secreted into the lymphatic system associated with CMs. In the blood circulation, CM particles undergo lipolysis, catalyzed by a lipoprotein lipase, resulting in the formation of CM remnants that are quickly taken up by the liver. In the liver, the remnant-associated carotenoid can be either (1) metabolized into vitamin A and other metabolites, (2) stored, (3) secreted with the bile, or (4) repackaged and released with VLDL particles. In the bloodstream, VLDLs are transformed to LDLs, and then HDLs by delipidation and the carotenoids associated with the lipoprotein particles are finally distributed to extrahepatic tissues (Figure 3.2.2). Time-course studies focusing on carotenoid appearances in different lipoprotein fractions after ingestion showed that CM carotenoid levels peak early (4 to 8 hr) whereas LDL and HDL carotenoid levels reach peaks later (16 to 24 hr). 

FIGURE 9. Endogenous lipoprotein metabolism. In liver cells, cholesterol and triglycerides are packaged into VLDL particles and exported into blood where VLDL is converted to IDL. Intermediate-density lipoprotein can be either cleared by hepatic LDL receptors or further metabolized to LDL. LDL can be cleared by hepatic LDL receptors or can enter the arterial wall, contributing to atherosclerosis. Acetyl CoA, acetyl coenzyme A Apo, apolipoprotein C, cholesterol CE, cholesterol ester FA, fatty acid HL, hepatic lipase HMG CoA, 3-hydroxy-3-methyglutaryl coenzyme A IDL, intermediate-density lipoprotein LCAT, lecithin-cholesterol acyltransferase LDL, low-density lipoprotein LPL, lipoprotein lipase VLDL, very low-density lipoprotein. 

Niacin (vitamin B3) has broad applications in the treatment of lipid disorders when used at higher doses than those used as a nutritional supplement. Niacin inhibits fatty acid release from adipose tissue and inhibits fatty acid and triglyceride production in liver cells. This results in an increased intracellular degradation of apolipoprotein B, and in turn, a reduction in the number of VLDL particles secreted (Fig. 9-4). The lower VLDL levels and the lower triglyceride content in these particles leads to an overall reduction in LDL cholesterol as well as a decrease in the number of small, dense LDL particles. Niacin also reduces the uptake of HDL-apolipoprotein A1 particles and increases uptake of cholesterol esters by the liver, thus improving the efficiency of reverse cholesterol transport between HDL particles and vascular tissue (Fig. 9-4). Niacin is indicated for patients with elevated triglycerides, low HDL cholesterol, and elevated LDL cholesterol.3... 

High-density lipoproteins (HDL) and very low-density lipoproteins (VLDL) are synthesized in the liver. LDL is produced in the blood stream as VLDL particles are partially delipidated by lipoprotein lipase, a triglyceride hydrolysing enzyme located on the luminal surface of vessels in sites such adipose tissue. 

The substrate for the LPL is the triglyceride contained within the oily core of VLDL particles and chylomicrons. The fatty acids and monoglycerides liberated from triglyceride hydrolysis are taken into the adipocytes and reformed into neutral fat for calorie storage (Figure 9.11). The ultimate result of the delipidation of VLDL and chylomicrons to the formation of low-density lipoproteins (LDL) as described in Section 5.5. 

The best-known effect of APOE is the regulation of lipid metabolism (see Fig. 10.13). APOE is a constituent of TG-rich chylomicrons, VLDL particles and their remnants, and a subclass of HDL. In addition to its role in the transport of cholesterol and the metabolism of lipoprotein particles, APOE can be involved in many other physiological and pathological processes, including immunoregu-lation, nerve regeneration, activation of lipolytic enzymes (hepatic lipase, lipoprotein lipase, lecithin cholesterol acyltransferase), ligand for several cell receptors, neuronal homeostasis, and tissue repair (488,490). APOE is essential... 

APO -2-containing remnants and VLDL particles are slowly removed from the plasma and induce an upregulation of the liver LDL receptor and subsequent low concentration of plasma cholesterol. NUAL-APOE-A particles are removed from plasma faster than VLDL-AL 0 -3 particles, inducing a dowm-egulation of the LDL receptor, and thus the NUAL-APOE-A phenotype is associated with a higher concentration of circulating cholesterol (488). 

The liver requires cholesterol for synthesizing VLDL particles and bile acids. Triglyceride-rich VLDL particles are released into the blood and, like the chylomicrons, supply other tissues with fatty acids. Left behind are LDL particles that either return into the liver or supply extrahepatic tissues with cholesterol. 

The elevation of HDL levels by fibrates may be due to two drug actions induced synthesis of apo-Al, the principal apoprotein of HDL, and increased assembly of new HDL particles in the circulation. Sirrface components of VLDL contribute to formation of HDL, as the VLDL particles are reduced in size through the action of LPL. The increased rate of catabolism of VLDL caused by the fibrates would provide more components for assembly of HDL particles. 

Release of VLDLs VLDLs are secreted directly into the blood by the liver as nascent VLDL particles containing apolipoprotein B-100. They must obtain apo C-ll and apo E from circulating HDL (see Figure 18.17). As with chylomicrons, apo C-ll is required for activation of lipoprotein lipase. [Note Abetalipoproteinemia is a rare hypolipoproteinemia caused by a defect in triacylglycerol transfer protein, leading to an inability to load apo B with lipid. As a consequence, no chylomicrons or VLDLs are formed, and tria-cylglycerols accumulate in the liver and intestine.]... 

Synthesis of lipids from carbohydrates is an efficient process, which occurs largely in the liver and also in intestinal epithelial cells.6 The newly synthesized triacylglycerols, together with smaller amounts of phospholipids and cholesterol, combine with specific apolipoproteins, which are also synthesized in the liver, to form very low density lipoprotein (VLDL) particles which are secreted into the blood stream. 

Both chylomicrons and VLDL particles undergo similar processes in the capillary blood vessels, where their triacylglycerols are hydrolyzed to glycerol and free fatty acids by lipoprotein lipase 40 42a This enzyme requires for its activity the apolipoprotein C-II which is present in the chylomicrons and VLDL particles. Lipoprotein lipase is also known as the "clearing... 

Liver and some intestinal cells export cholesterol into the bloodstream, together with triacylglycerols and phospholipids in the form of VLDL particles, for uptake by other tissues (see Fig. 21-1). Cholesteryl esters are formed in the ER by lecithin cholesterol acyltransferase (LCAT), an enzyme that transfers the central acyl group from phosphatidylcholine to the hydroxyl group of cholesterol.191 1913 This enzyme is also secreted by the liver and acts on free cholesterol in lipoproteins.192 Tissue acyltransferases also form cholesteryl esters from fatty acyl-CoAs.192a... 

As mentioned in Chapter 21, there are several related receptors with similar structures. Two of them have a specificity for apolipoprotein E and can accept remnants of VLDL particles and chylomicrons.216 220 The LDL receptor-related protein is a longer-chain receptor.216 221 LDL particles, especially when present in excess or when they contain oxidized lipoproteins, may be taken up by endocytosis into macrophages with the aid of the quite different scavenger receptors.221 225 The uptake of oxidized lipoproteins by these receptors may be a major factor in promoting development of atherosclerosis (Box 22-B). On the other hand, scavenger receptor SR-B1, which is also present in liver cells, was recently identified as the receptor for HDL and essential to the "reverse cholesterol transport" that removes excess cholesterol for excretion in the bile.213/213a... 

Acute steatosis of the liver may have explained this presentation. In insulin overdose, the combination of greatly increased hepatic production of triglycerides from glucose and reduced production of apolipoprotein B 100 results in an insufficient increase in the transport of triglycerides in VLDL particles from liver to muscle and adipose tissue and contributes to the steatosis. 

The size of the VLDL particle in plasma diminishes and its density increases as triglyceride is hydrolyzed by endothelial lipoprotein lipase, and the particles are thus converted to intermediate-density lipoproteins (IDL) (B32, S35). The IDL detach from the endothelium, and some are taken up by hepatic B-100, E receptors. The remaining particles in the circulation are further depleted of some cholesteryl ester (by an unknown mechanism), and most of the remaining triglyceride (probably by hepatic triglyceride lipase, in the liver sinusoids) (D5). Hie resulting LDL particles are largely composed of cholesteryl ester as the core lipid and apoB-100 as the apolipoprotein. 

In hepatocytes, vitamin E can take two routes. A fraction of it is packaged as VLDL and reenters the circulation, while excess is excreted in the bile. Plasma lipolysis of the VLDL particle again results in release not only of lipids, but also of vitamin E, with the remainder left with the LDL particles. This fraction can be further distributed to tissues via LDL receptor-mediated endocytosis or transferred between lipoproteins, mainly to HDL, by plasma lipid transfer proteins. Thus, mobilization of vitamin E from intestinal and liver... 

VLDL particles are assembled in the liver and consist of triglycerides (50-60%) and cholesterol. These particles leave the liver, where the... 

VLDL, IDL and LDL. VLDL particles are released by the liver and are rich in triglycerides and cholesterol. VLDL particles, like the chylomicrons, drop off their triglycerides in fat and muscle cells. The remainder of the particles become cholesterol rich LDL particles (after going through an intermediate IDL stage). LDL distributes the chole.sterol widely to hepatic and iioa-l)cpatic cells... 

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