Intermediate density metabolism

Figure 25-4. Metabolic fate of very low density lipoproteins (VLDL) and production of low-density lipoproteins (LDL). (A, apolipoprotein A B-100, apolipoprotein B-100 , apolipoprotein C E, apolipoprotein E HDL, high-density lipoprotein TG, triacylglycerol IDL, intermediate-density lipoprotein C, cholesterol and cholesteryl ester P, phospholipid.) Only the predominant lipids are shown. It is possible that some IDL is also metabolized via the LRP.

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. 

Partial summary of lipoprotein metabolism in humans. I to VII are sites of action of hypolipidemic drugs. I, stimulation of bile acid and/or cholesterol fecal excretion II, stimulation of lipoprotein lipase activity III, inhibition of VLDL production and secretion IV, inhibition of cholesterol biosynthesis V, stimulation of cholesterol secretion into bile fluid VI, stimulation of cholesterol conversion to bile acids VII, increased plasma clearance of LDL due either to increased LDL receptor activity or altered lipoprotein composition. CHOL, cholesterol IDL, intermediate-density lipoprotein. 

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...

Soutar, A. K., Myant, N. B., and Thompson, G. R., The metabolism of very low density and intermediate density lipoproteins in patients with familial hypercholesterolaemia. Atherosclerosis 43, 217-231 (1982). 

Figure 19.3 Lipoprotein metabolism in the human being. Details of HDL metabolism have been omitted. LPL, lipoprotein lipase FFA, free fatty acids CM, chylomicrons A-E, apoproteins A-E HDL, LDL, IDL, and VLDL are high-density, low-density, intermediate-density, and very low density lipoproteins. (Reproduced by permission from Staff writers. Heart-liver transplantation in a child with homozygous familial hypercholesterolemia. Nutr Rev 43 274-278, 1985.)...

Metabolism of plasma lipoproteins and related genetic diseases. CM=chylomicron, TG=triacylglycerol, VLDL=very low density lipoprotein, LDL=low density lipoprotein, IDL=intermediate density lipoprotein, apo Cll= apolipoprotein Cl I found in chylomicrons and VLDL. The Roman numerals in the white circles refer to specific genetic types of hyperlipidemias summarized on the facing page. 

Remnant removal disease (RRD, also called remnant lipaemia, familial dysbetalipoproteinemia) (uncommon) in which there is a defect of apolipoprotein E. This is the major ligand that allows internalisation and subsequent metabolism of remnant particles derived from VLDL and chylomicrons. The consequence is accumulation of VLDL remnants called intermediate density lipoprotein (IDL) with cholesterol and triglycerides usually in the range 6-9 mmol/1. Patients experience severe macrovascular disease (as above). 

Hepatic lipase is involved in the metabolism of high-density lipoproteins and intermediate density lipoproteins (IDLs), converting the HDL2 fraction to HDL3 and generating LDLs from IDLs. The enzyme appears to have broad specificity it hydrolyzes tri-, di-, and mono-acylglycerols, acyl-CoA thioesters, and even phospholipids. hHL is secreted by the liver parenchymal cells and does not require any cofactors for its activity. 

Figure 26-19 Endogenous lipoprotein metabolism pathway. TG, Triglyceride CE, cholesterol ester FC, free cholesterol PL, phospholipids HDL, high-density lipoproteins LDL low-density lipoproteins IDL, intermediate-density lipoproteins VLDL very low-density lipoproteins FA, fatty acid LPL, lipoprotein lipase LCAL lecithin cholesterol acyltransferase B, apolipoproteln B-tOO A, apolipoprotein A-l C, apolipoprotein C-fl , apofipoprotein E. (From RIfai N. Lipoproteins and apolipoproteins Composition, metabolism, and association with coronary heart disease. Arch Pathol Lab Med 1986 110 694-701. Copyright 1986, American Medical Association.)...

C-III, and phospholipids are transferred to EfDL. Apolipoproteins E and C-II are transferred to chylomicrons from EfDL and evenmally back through these metabolic events. Hepatic VLDL synthesis is regulated in part by diet and hormones and is inhibited by uptake of chylomicron remnants in the liver. VLDL is secreted from the Ever and serially converted via LPL to intermediate-density hpoprotein (IDL) and finally to LDL. VLDL receptors are found in adipose tissue and muscle and bear close homology to the structure of LDL receptors. 

Consequently, the apo B particle gradually becomes smaller, and denser. Functionally, very low-density lipoproteins (VLDLs, density <1.006 g/ml), intermediate density lipoproteins (IDLs, density 1.006-1.019 g/ml), and low-density lipoproteins (LDLs, density 1.019-1.063) represent a continuum created by the lipolysis of TG. Some IDL and all of LDL are cleared from the circulation by the liver. Residual lipids may be recycled in the form of new VLDL particles, or be catabolized and secreted into bile. While there are differences in the metabolism in the plasma of chylomicrons from the intestine, and VLDL from the liver, the same lipases are involved in both cases. 

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.

FIGURE 35-1 The miyor pathwi s involved in the metabolism of chylomicrons synthesized by the intestine and VLDL synthesized by the liver. Chylomicrons are converted to chylomicron remnants by the hydrolysis of their triglycerides by LPL. Chylomicron remnants are rapidly cleared from the plasma by the liver. Remnant receptors include die LDL receptor-related protein (LRP), LDL, and perhaps other receptors. FFA released by LPL is used by muscle tissue as an energy source or taken up and stored by adipose tissue. FFA, free fatty acid HL, hepatic lipase IDL, intermediate-density lipoproteins LDL, low-density lipoproteins LPL, lipoprotein lipase VLDL, very-low-density lipoproteins. 

VLDL is metabolized via intermediate density lipoprotein (IDL) to LDL in the plasma by the action of lipoprotein lipase [72], Hepatic lipase may also contribute to the formation of TG-rich LDL particles [73], The increased production/decreased clearance of VLDL also may result in the increased production of precursors of small dense LDL (sd-LDL) particles [57,74,75], Such sd-LDL particles have been shown to contribnte to vascnlar diseases, as LDL receptors have a reduced affinity for sd-LDL, and sd-LDL are more vulnerable to oxidative modification [76-78], Numerous clinical stndies have shown increased CVD in subjects with high prevalence of sd-LDL [79], In animal models and in human diabetic conditions, sd-LDL levels are elevated [80,81] and snch accumulation appears to be accompanied by decreased paraoxonase 1 (PONl) activity. PONs are antioxidant enzymes that are known to detoxify H2O2 and lipid peroxides [82,83], The presence of PONl in lipoproteins also protects the... 

Figure 13.2. Metabolism of lipoproteins. From Gurr (1997) with permission. CE, eholesteryl esters HDL, high density lipoprotein whieh is intereonverted into two forms, HDL and HDL3 VLDL, very low density lipoprotein IDL, intermediate density lipoprotein LDL, low density lipoprotein, LCA, leeithin eholesterol aeyltransferase (see Figure 13.3).

Scheme 113.1 Schematic overview of cholesterol metabolism and main proposed mechanisms of action of phytosterols. 1. The absorption of dietary and/or biliary cholesterol is reduced by competition with PS for incorporation into mixed micelles. 2. Esterification of free cholesterol in the enterocyte is reduced by competition with PS for ACAT-2 enzyme. 3. Upregulation of the heterodimer ABCG5/G8 by PS can increase intestinal and hepato-biliar secretion. 4. Upregulation of ABCAl by PS can increase the incorporation of sterols into nascent HDL. 5. Increased cholesterol excretion via TICE. 6. Although it is not directly mediated by PS, the lower levels of hepatic cholesterol can lead to a lower VLDL secretion and upregulation of LDL receptor, which improves the clearance of plasma cholesterol. Abbreviations FC free cholesterol, CE cholesterol esters, ACAT-2 Acyl-CoA cholesterol O-acyltransferase 2, CM chylomicron, CMR chylomicron remnant, TICE transintestinal cholesterol efflux, LDL low-density lipoprotein, IDL intermediate-density lipoprotein, HDL high-density lipoprotein...

Figure 4. An overview of lipoprotein metabolism. HDL, high density lipoprotein. IDL, intermediate density lipoprotein. LDL, low density lipoprotein. NEFA, non-esterified fatty add. VLDL, very low density lipoprotein. 1, lipoprotein lipase. 2, hepatic lipase. 3, LDL receptor. 4, cholesterol ester transfer...

Fig. 28.1. A schematic diagram depicting lipoprotein metabolism and the known genetic defects affecting lipoproteins. 28.1, Lipoprotein lipase (LPL) deficiency 28.2, apoC-II deficiency 28.3, apoE deficiency or mutations 28.4, hepatic lipase (HL) deficiency 28.5, LDL receptor deficiency or mutations 28.6, apoB-100 mutation in receptor binding region 28.7, apoA-I deficiency or mutations 28.7.3, ABCAl deficiency or mutations 28.8, LCAT deficiency 28.9, microsomal transfer protein (MTP) deficiency 28.10, apoB-100 synthesis or truncation mutations. Abbreviations C-II, apoC-II B, apoB E, apoE A-I, apoA-I VLDL, very-low-density lipoproteins IDL, intermediate-density lipoproteins LDL, low-density lipoproteins HDL, high-density lipoproteins LPL, lipoprotein lipase HL, hepatic lipase LCAT, lecithin cholesterol acyltransferase UC, unesterified cholesterol...

VLDL assembly and secretion is similar to the corresponding pathway for chylomicrons. Triglycerides and cholesterol esters are packaged into the core of the lipoprotein particle. However, in contrast to intestinal chylomicron secretion, hepatocytes secrete VLDL directly into the bloodstream. In the bloodstream, VLDL is acted upon by lipoprotein lipase, delivering its triglyceride cargo to muscle and adipose tissue. The resulting VLDL remnant particle, also termed IDL (intermediate density lipoprotein), is further metabolized as discussed below. 

Figure 25-7. Metabolism of adipose tissue. Hormone-sensitive lipase is activated by ACTH, TSH, glucagon, epinephrine, norepinephrine, and vasopressin and inhibited by insulin, prostaglandin E, and nicotinic acid. Details of the formation of glycerol 3-phosphate from intermediates of glycolysis are shown in Figure 24-2. (PPP, pentose phosphate pathway TG, triacylglycerol FFA, free fatty acids VLDL, very low density lipoprotein.)...

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