Lipoprotein removal from plasma

Lipoproteins (from human plasma). Individual human plasma lipid peaks were removed from plasma by ultracentrifugation, then separated and purified by agarose-column chromatography. Fractions were characterised immunologically, chemically, electrophoretically and by electron microscopy. [Rudel et al. Biochem J 13 89 1974.]... 

The major function of LTP-I in human plasma may be to distribute es-terified cholesterol from the HDL fraction, where cholesterol is esterified, to other lipoprotein fractions. LCAT activity is responsible for the production of some 50-100 nmol esterified cholesterol per milliliter of plasma per hour (Gil). The concentration of esterified cholesterol in human HDL is about 1000 nmol/ml of plasma. Only 0.5-1.0% of HDL apoprotein is removed from plasma per hour (B41), probably mainly in intact HDL particles. If so, then the uptake of HDL particles can account for the removal from plasma of only about 10-20% of the esterified cholesterol formed in HDL in the LCAT reaction. 

It is, of course, also possible that the esterified cholesterol formed in HDL may be removed from plasma by some process other than uptake of the whole HDL particle or LTP-I-mediated transfer to other lipoprotein particles, but this possibility has not been fully investigated. Some evidence that there may be other pathways than these for the removal from plasma of HDL esterified cholesterol comes from the studies of Class et al. (G5, G6), who showed that cholesteryl ether incorporated in rat HDL as a tracer for cholesteryl ester was taken up in vivo by the rat liver (and by other organs) fester than apoA-I tracer (see Section 4.1.2). These studies are complicated by the relatively high concentration of apoE in rat HDL (compared, for instance, to man) and the unknown effect of apoE on HDL cholesteryl ester metabolism in the rat. Further studies on the removal of esterified cholester-... 

Gemfibrozil reduces the synthesis of VLDL and, to a lesser extent, apolipoprotein B with a concurrent increase in the rate of removal of triglyceride-rich lipoproteins from plasma. Clofibrate is less effective than gemfibrozil or niacin in reducing VLDL production. 

Details of plasma lipoproteins and their metabolism are given in Section 5.5. Most of the cholesterol in the blood is carried as part of low density lipoprotein (LDL) or high density lipoprotein (HDL), whereas most triglyceride, in the fasting state, is carried by very low density lipoprotein (VLDL). The relative concentrations of these lipoproteins constitute the lipid profile and determine CVD risk. Diabetics are more likely to show an unhealthy profile with elevated concentrations of LDL and triglyceride but reduced HDL concentration. This pattern can be partly explained by enhanced fatty acid liberation from adipocytes as a consequence of insulin resistance in that tissue and due to reduced removal from the circulation of triglycerides, which is also insulin dependent. 

Drugs that lower the concentration of lipoproteins in the plasma by inhibiting their production in the organism or by removing them from the plasma are called hypolipidemic or antisclerotic drugs. 

Mechanism of Action An antihyperlipoproteinemic that binds with bile acids in the intestine, forming an insoluble complex. Binding results in partial removal of bile acid from enterohepaticcirculat ion. Tiierapeutic Effect Removes low-density lipoproteins (LDL) and cholesterol from plasma. 

The HDL lipids are removed from the circulation by a selective uptake and by an indirect pathway. The selective uptake of cholesterol esters from HDL into he-patocytes and steroidogenic cells is mediated by the binding of HDL to scavenger receptor B1 (SR-BI). This selective uptake by SR-BI may depend on the presence of cofactors such as HL, which hydrolyses phospholipids on the surface of both HDL and plasma membranes and thereby enables the flux of cholesteryl esters from the lipoprotein core into the plasma membrane [42]. The indirect pathway involves the enzyme CETP, which exchanges cholesteryl esters of a-HDL with triglycerides of chylomicrons, VLDL, IDL, and LDL. The a-HDL derived cholesteryl esters are therefore removed via the LDL-receptor pathway. The removal of excess cholesterol from the periphery and the delivery to the liver for excretion in the bile is termed reverse cholesterol transport. 

Lipoproteins Are Made in the Endoplasmic Reticulum of the Liver and Intestine Chylomicrons and Very-Low-Density Lipoproteins (VLDLs) Transport Cholesterol and Triacylglycerol to Other Tissues Low-Density Lipoproteins (LDLs) Are Removed from the Plasma by the Liver, Adrenals, and Adipose Tissue... 

As the lipoproteins are depleted of triacylglycerol, the particles become smaller. Some of the surface molecules (apoproteins, phospholipids) are transferred to HDL. In the rat, remnants that result from chylomicron catabolism are removed by the liver. The uptake of remnant VLDL also occurs, but much of the triacylglycerol is further degraded by lipoprotein lipase to give the intermediate-density lipoprotein (IDL). This particle is converted into LDL via the action of lipoprotein lipase and enriched in cholesteryl ester via transfer from HDL by the cholesteryl ester transfer protein. The half-life for clearance of chylomicrons from plasma of humans is 4-5 min. Patients with the inherited disease, lipoprotein lipase deficiency, clear chylomicrons from the plasma very slowly. When on a normal diet, the blood from these patients looks like tomato soup. A very-low-fat diet greatly relieves this problem. 

Low-Density Lipoproteins (LDLs) Are Removed from the Plasma by the Liver, Adrenals, and Adipose Tissue... 

Schneider, W. J., Removal of lipoproteins from plasma. In D. E. Vance, and J. E. Vance (eds.), Biochemistry of Lipids, Lipoproteins and Membranes. Amsterdam Elsevier Science Publishers, 1991. This chapter (16) provides a clear explanation of the current literature on the uptake of lipoproteins into cells and tissues. 

CM and VLDL secreted by intestinal cells and VLDL synthesized and secreted in the liver have similar metabolic fates. After secretion into the blood, newly formed CM and VLDL take up apoprotein (apo-C) from HDL and are subsequently removed from the blood (plasma half-life of less than 1 h in humans [137]) primarily by the action of lipoprotein lipase (LPL). Lipoprotein lipase is situated mainly in the vascular bed of the heart, skeletal muscle, and adipose tissue and catalyzes the breakdown of core TG to monoglycerides and free fatty acids, which are taken up into adjacent cells or recirculated in blood bound to albumin. The activity of LPL in the heart and skeletal muscle is inversely correlated with its activity in adipose tissue and is regulated by various hormones. Thus, in the fasted state, TG in CM and VLDL is preferentially delivered to the heart and skeletal muscle under the influence of adrenaline and glucagon, whereas in the fed state, insulin enhances LPL activity in adipose tissue, resulting in preferential uptake of TG into adipose tissue for storage as fat. 

The main precursors of plasma HDL are most likely disk-shaped bilayers composed of PL and protein and secreted by the liver and intestine. HDL are also derived from the surplus surface material removed from TG-rich lipoproteins during lipolysis. HDL are involved in the net transfer of cholesterol from peripheral tissues to the liver, where it can be eliminated or recirculated. This process is initiated by the uptake of FC from cell membranes into the HDL. The nature of this uptake is not known but may involve binding of HDL to the membrane. 

It should also be remembered that plasma lipoproteins are constantly in a state of metabolic flux. Some large particles are converted to smaller particles, and vice versa. Lipids and most apolipoproteins exchange or are transferred between particles and particles are released into and removed from the circulation. 

Correct answer = D. Clofibrate and gemfibrozil Increase the activity of lipoprotein lipase, thereby increasing the removal of VLDL from plasma. Niacin inhibits lipolysis in adipose tissue and thus eliminates the building blocks needed by the liver to produce triacylglycerol and there-... 

Chylomicron remnants and very low density lipoprotein (VLDL) remnants are rapidly removed from the circulation by receptor-mediated endocytosis. ApoE, the major apolipoprotein of the chylomicron in the brain, binds to a specific receptor and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. Defects in apolipoprotein E result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants (Mahley et al., 1999). In the brain, lipidated apoE binds aggregated in a isoform-speciflc manner, apoE4 being much more effective than the other forms,... 

Since lipid (lipoprotein) inhibit lysis, agents that lower lipid levels have a normalizing effect on decreased fibrinolysis activity due to elevated lipids. Even the removal of normal lipid content from plasma with chloroform increases lysis activity. Vasoactive agents have previously been reported61 to stimulate activator release resulting in enhanced lysis activity of short duration. 

Etiology of Type II Hyperlipoproteinemia - In a study of the inheritance of xanthomatosis and hyper- -lipoproteinemia, the segregation pattern satisfied the criteria for autosomal dominant inheritance, but not for a polygenic trait. The genetic analysis demonstrated that hyperlipoproteinemia Type Ila and Type lib were the same disease.7 8 Defective removal of low density lipoproteins (LDL) from the circulation produced the elevated LDL and plasma cholesterol observed in Type II hyperlipoproteinemia. This defect appeared to be related to the decreased number of LDL receptors on cell surfaces (for reviews see 9, 10), although a change in the permeability of the cell membrane to cholesterol may also play a prominent role. 

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