Reverse lipid transport

Whole plasma can also be fractionated into specific lipoprotein size classes to further resolve the underlying biochemistry and metabolism of tissues that deliver these lipids to blood and selectively remove them. Thus, TrueMass analysis can be used to measure the lipid profiles of very-low-density lipoprotein, quantify the lipid pathways responsible for metabolic changes in the liver and measure profiles of high-density lipoprotein to quantify the flux of lipids in reverse cholesterol transport. 

Paramagnetic analogs of phospholipids have also been used to investigate lipid transport phenomena in model membrane systems (R.D. Komberg, 1971) and in biological membranes. Representative structures are shown in Fig. 2. Several of these spin-labeled lipid analogs that are modified in the fatty acid chain can be readily and reversibly transferred... 

Plate 17. Summary of major forward and reverse lipid transport pathways through the extracellular compartment that link the liver and intestine with peripheral tissues. FC, unesterified cholesterol. For other abbreviations see list of abbreviations. (See page 536 in this volume.)... 

Reverse lipid transport is the movement of lipids, mainly cholesterol and phospholipids, from peripheral tissues, through the extracellular compartment, to the liver for catabolism. Unlike the forward transport of lipids, that involves mainly TG packaged into lipoproteins inside hepatic and intestinal cells, the cholesterol and phospholipids contributing to reverse transport are assembled into lipoproteins extracellularly, as the result of events in the plasma. 

Water-soluble compounds are naturally easily transported in the blood. Non-soluble compounds are usually transported bound to plasma proteins (albumins). This binding is reversible in most cases but may vary remarkably. The degree of protein binding may vary between 50% and 99%. The proportion of the free (unbound) compound in the circulation is the amount of the compound that can reach the tissues and thus the target organs. Very lipid-... 

Four major groups of lipoproteins are recognized Chylomicrons transport lipids resulting from digestion and absorption. Very low density lipoproteins (VLDL) transport triacylglycerol from the liver. Low-density lipoproteins (LDL) deliver cholesterol to the tissues, and high-density lipoproteins (HDL) remove cholesterol from the tissues in the process known as reverse cholesterol transport. 

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by pre 3 HDL binding to the ABC-1 transporter protein via apo A-l. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol CE, cholesteryl ester PL, phospholipid ACAT, acyl-CoA cholesterol acyltransferase LCAT, lecithinicholesterol acyltransferase A-l, apolipoprotein A-l LDL, low-density lipoprotein VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

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... 

Hepatic steatosis usually is a result of excessive administration of carbohydrates and/or lipids, but deficiencies of carnitine, choline, and essential fatty acids also may contribute. Hepatic steatosis can be minimized or reversed by avoiding overfeeding, especially from dextrose and lipids.35,38 Carnitine is an important amine that transports long-chain triglycerides into the mitochondria for oxidation, but carnitine deficiency in adults is extremely rare and is mostly a problem in premature infants and patients receiving chronic dialysis. Choline is an essential amine required for synthesis of cell membrane components such as phospholipids. Although a true choline deficiency is rare, preliminary studies of choline supplementation to adult patients PN caused reversal of steatosis. 

Bailey, KR, Ishida, BY, Duncan, KG, Kane, JP, and Schwartz, DM, 2004. Basal reverse cholesterol transport of retinal pigment epithelium cell digested photoreceptor outer segment lipids. Invest Ophthalmol Vis Sci 45, U721. 

The exit of drugs from the CNS can involve (1) diffusion across the blood-brain barrier in the reverse direction at rates determined by the lipid solubility and degree of ionization of the drug, (2) drainage from the cerebrospinal fluid (CSP) into the dural blood sinuses by flowing through the wide channels of the arachnoid villi, and (2) active transport of certain organic anions and cations from the CSF to blood across the choroid plexuses... 

Low HDL cholesterol (<35 mg/dL) is an independent risk factor for CHD. HDL appears to antagonize atherogenesis by at least two mechanisms. HDL can mobilize cholesterol from extrahepatic cells (such as arterial wall foam cells) and transport it to the liver for disposal (reverse cholesterol transport) HDL also has antioxidant properties. HDL contains the potent antioxidant enzyme paraoxonase, which may protect LDL lipids from oxidation. Thus, hypertriglyceridemia with... 

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. 

HDL may be taken up in the liver by receptor-mediated endocytosis, but at least some of the cholesterol in HDL is delivered to other tissues by a novel mechanism. HDL can bind to plasma membrane receptor proteins called SR-BI in hepatic and steroidogenic tissues such as the adrenal gland. These receptors mediate not endocytosis but a partial and selective transfer of cholesterol and other lipids in HDL into the cell. Depleted HDL then dissociates to recirculate in the bloodstream and extract more lipids from chylomicron and VLDL remnants. Depleted HDL can also pick up cholesterol stored in extrahepatic tissues and carry it to the liver, in reverse cholesterol transport pathways (Fig. 21-40). In one reverse transport path, interaction of nascent HDL with SR-BI receptors in cholesterol-rich cells triggers passive movement of cholesterol from the cell surface into HDL, which then carries it back to the liver. In a second pathway, apoA-I in depleted HDL in-... 

Bile acids are sterol derivatives derived from cholesterol that have two major functions. (l) The cholesterol delivered back to the liver by reverse cholesterol transport is converted into bile acids, which are excreted from the body via the intestine. (2) The bile acids secreted into the intestine are required for the solubilization of dietary lipids so that they can be degraded by lipases and absorbed into the intestinal wall (see fig. 18.2). 

A, Inhibition of proteolytic enzymes B, dissociation of hexameric to monomeric form of insulin C, loosening of tight junctions D, increase in membrane fluidity due to cholesterol removal E, reversible ciliostasis F, mucoadhesion and prolonged residence time G, incorporation into lipid bilayer and membrane perturbation H, insulin internalization, increased transcellular transport and I, correlation with CMC. 

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