Lipoproteins clearance

Despite inhibition of HMG-CoA reductase by statins, cells compensate by increasing enzyme expression several fold. However, the total body cholesterol is reduced by 20-40% due to increased expression of LDL-receptors after statin administration this enhances LDL (the major cholesterol carrying lipoprotein) clearance from serum with a net reduction of serum cholesterol (Chapter 20). Individuals who lack functional LDL-receptors (homozygous familial hypercholesterolemia. Chapter 20) do not benefit from statin therapy. However, statin therapy is useful in the treatment of heterozygous familial hypercholesterolemia. Since HMG-CoA reductase plays a pivotal role in the synthesis of many products vital for cellular metabolism, inhibitors of the enzyme may have toxic effects. Monitoring of liver and muscle function may be necessary to detect any toxicity of statin drug therapy. A decreased risk of bone fractures with statin therapy has been observed in subjects age 50 years or older, who are being treated for hypercholesterolemia. The mechanism of action of statins in bone metabolism may involve inhibition of prenylation... 

Ji ZS, Sanan DA, Mahley RW (1995) Intravenous hepaiinase inhibits remnant lipoprotein clearance from the plasma and uptake by the liver in vivo role of heparan sulfate proteoglycans. J Lipid Res 36 583-592... 

Ishibashi S, Herz J, Maeda N, Goldstein JL, Brown MS (1994) The two-receptor model of lipoprotein clearance Tests of the hypothesis in knockout mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins. Proc Natl Acad Sci USA 91 4431-4435... 

To enhance lipid particle clearance by acting as a cofactor for the lipoprotein lipase enzyme... 

The answer is a. (Katzung, p 590.) Bile acids are absorbed primarily in the ileum of the small intestine. Cholestyramine binds bile acids, preventing their reabsorption in the jejunum and ileum. Up to 10-fold greater excretion of bile acids occurs with the use of resins. The increased clearance leads to increased cholesterol turnover of bile acids. Low-density lipoprotein receptor upregulation results in increased uptake of LDL. This does not occur in homozygous familial hypercholesterolemia because of lack of functioning receptors. 

TLR2 -/- decreased clearance of Borrelia burgdorferi lipoproteins greater susceptibility to S. aureas... 

The pulmonary lymphatic system contributes to the clearance of fluid and protein from the lung tissue interstitium and helps to prevent fluid accumulation in the lungs [108], The lymphatic endothelium allows micron-sized particles (e.g. lipoproteins, plasma proteins, bacteria and immune cells) to pass freely into the lymph fluid [103], After administration of aerosolised ultrafine particles into rats, particles were found in the alveolar walls and in pulmonary lymph nodes [135], which suggests that drainage into the lymph may contribute to the air-to-blood transport of the inhaled particles. 

As discussed above, insulin suppresses the breakdown of triglyceride within fat cells in the post-prandial period, preventing release of fatty acids from adipocytes in healthy individuals. Insulin also stimulates triglyceride clearance from triglyceride-rich lipoprotein particles and the esterification of fatty acids to form the intra-adipocyte triglyceride store. 

Finally, dyslipidemia is a feature of FXR knockout mice levels of VLDL, LDL and HDL cholesterol and ApoB lipoproteins are increased concomitant with reduced clearance of HDL cholesteryl ester and elevated triglyceride and free fatty-acid levels. ... 

Pharmacokinetics Ticlopidine is rapidly absorbed (more than 80%), with peak plasma levels occurring at approximately 2 hours after dosing, and is extensively metabolized. Administration after meals results in a 20% increase in the area under the plasma concentration-time curve (AUC). Ticlopidine displays nonlinear pharmacokinetics and clearance decreases markedly on repeated dosing. Ticlopidine binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein at concentrations attained with the recommended dose, 15% or less in plasma is bound to this protein. 

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. 

An increased rate of metabolic clearance has been observed after removal of sialic acid from human, low-density lipoprotein in vivo.472 Sialic acid controls the receptor-mediated uptake of this lipoprotein by fibroblasts. Removal of sialic acid residues accelerates the rate of internalization of the lipoprotein and, subsequently, the regulation of the metabolism of cellular cholesterol.473... 

The LDL particles contain one apoB-100 as the structural protein and are the major cholesterol-transporting lipoproteins in human blood. Clearance of LDL from blood is mediated by the interaction of apoB-100 with the LDLR. Genetic defects either in the receptor binding region of apoB-100 or in the LDLR lead to decreased clearance of LDL and hence to their accumulation in the blood. The major metabolic pathways of the lipoprotein metabolism are shown in Fig. 5.2.1. 

Production of LDL from VLDL in the plasma With these modifications, the VLDL is converted in the plasma to LDL. An intermediate-sized particle, the intermediate-density lipoprotein (IDL) or VLDL remnant, is observed during this transition. IDLs can also be taken up by cells through receptor-mediated endocytosis that uses apo E as the ligand. [Note Apolipoprotein E is normally present in three isoforms, E2, E3, and E4. Apo E2 binds poorly to receptors, and patients who are homozygotic for apo E2 are deficient in the clearance of chylomicron remants and IDLs. The individuals have familial type III hyperlipoproteinemia (familial dysbetalipoproteinemia, or broad beta disease), with hypercholesterolemia and premature atherosclerosis. Not yet understood is the fact that the E4 isoform confers increased susceptibility to late-onset Alzheimer disease.]... 

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. 

LRP is a member of the LDL receptor gene family (ref. 649) and, like the LDL receptor, performs an essential role in the removal of certain lipoprotein particles from the bloodstream. As Heeren et al. (ref. 650) explain, triglycerides are transported mainly by two distinct classes of lipoproteins, the chylomicrons and the very-low-density lipoproteins (VLDL). After assembly in the intestine, chylomicrons are carried via lymph into the bloodstream, where they are transformed at the endothelial surface to remnant lipoproteins through the catalytic action of lipoprotein lipase (for review, see ref. 651,652). After lipolysis, the lipoprotein lipase remains associated with the chylomicron remnants and, in conjunction with apolipoprotein E (apo E) (ref. 653-655), facilitates their clearance by the liver into hepatocytes (ref. 656) via LDL receptors and the LRP (ref. 657-660). (The essential role for both receptors in chylomicron remnant removal in vivo has been demonstrated in gene knockout and gene transfer experiments (ref. 661,662 for review, see ref. 663).)... 

Current opinion suggests that after emptying into the bloodstream, drugs associated with lymph lipoproteins equilibrate across the various plasma lipoprotein and protein fractions and take on the same clearance properties as drug introduced into the systemic circulation by way of the portal blood. The data of Haus et al. suggest that this is an oversimplification and that the mechanism of interconversion and interaction of dmg molecules between lymph and plasma lipoproteins is not clear [123],... 

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