Lipoprotein uptake regulation

The only receptor-mediated uptake process regulated in macrophages involves suppression of )8-VLDL receptors. This suppression only occurs after extensive cholesterol ester accumulation and can be induced by either j8-VLDL or chemically modified LDL [13]. Lipoprotein uptake by all known receptor systems in macrophages causes a marked stimulation of ACAT activity which results in the massive accumulation of cholesteryl ester droplets in the cytoplasm [13]. Free cholesterol can be excreted from the macrophage if cholesterol-accepting Upoproteins such as HDL are present. The uncontrolled uptake and deposition of cholesteryl esters in macrophages is believed to be the key to formation of the foam cells which are associated with atherosclerosis. 

In contrast to the extensive literature on the regulation of intestinal cholesterol synthesis, only a few studies are available on regulation of lipoprotein uptake in this organ. Notably, recent studies have compared the effect of various interventions such as the feeding of cholesterol, cholestyramine, surfomer, and com oil on both rates of cholesterol synthesis and LDL transport in the rat intestine in vivo, as shown in Fig. 9. While these various manipulations all alter rates of cholesterol synthesis, there is no consistent effect upon LDL uptake at any location in the mucosa, with the possible exception of a slight increase in the jejunum after feeding... 

Lipid homeostasis is dependent on the interaction between receptor mediated and enzymatic reactions that regulate cholesterol and triglycerides. Receptor mediated lipoprotein uptake occurs through different mechanisms ... 

More general information about the potential role of apoE in cellular lipoprotein uptake has come from studies with cultured cells (e.g., fibroblasts). Such cells manifest surface receptors for LDL that bind apoB, the protein component of LDL. This is followed by receptor-mediated endocytosis, fusion of the endo-cytic vesicles with lysosomes, and LDL degradation within the lysosomes (see Goldstein and Brown, 1979 Brown et al., 1981, for reviews and references). Cholesteryl esters taken into cells in this manner are hydrolyzed by a lysosomal acid lipase. The liberated cholesterol then leaves the lysosome and is used in the cell for membrane synthesis and as a regulator of intracellular cholesterol homeostasis. 

Vitamin E is delivered to tissues by three mechanisms transfer from triglyceride-rich lipoproteins during lipolysis as a result of tissue lipoprotein uptake by various receptors that mediate lipoprotein uptake and as a result of vitamin E exchange between lipoproteins or tissues. The regulation of tissue vitamin E is not well understood, but a-tocopherol is the predominant form in tissues as a result of its dominance in plasma. 

Despite the feasibility of using cultured RPE cells for studies similar to those performed using Caco-2 cells, the role of the RPE in carotenoid uptake and dynamic regulation has only just begun to be investigated. As carotenoids are carried in blood by lipoproteins, lipoprotein-rich serum seems to be the most appropriate vehicle for carotenoid delivery to cultured RPE cells. Indeed, recent studies comparing carotenoid delivery from fetal calf serum and from organic solvents showed that delivery in the presence of serum was superior to tetrahydrofuran (Shafaa et al., 2007). 

The bulk of pinocytosis in the nervous system is mediated by clathrin-mediated endocytosis (CME) [55] and this is the best-characterized pathway. More detail about clathrin-mediated pathways will be given when receptor-mediated endocytosis and the synaptic vesicle cycle pathways are considered. Pinocytosis through CME is responsible for uptake of essential nutrients such as cholesterol bound to low density lipoprotein (LDL) and transferring, but also plays a role in regulating the levels of membrane pumps and channels in neurons. Finally, CME is critical for normal synaptic vesicle recycling. 

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... 

Merkel M, Eckel RH, Goldberg IJ (2002) Lipoprotein lipase genetics, lipid uptake, and regulation. J Lipid Res 43 1997-2006... 

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. 

W17. Windier, E., Chao, Y., and Havel, R. J., Regulation of the hepatic uptake of triglyceride-rich lipoproteins in the rat. Opposing effects of homologous apolipoprotein E and individual C apoproteins. J. Biol. Chem. 255, 8303-8307 (1980). 

Cholesteryl esters that are internalized via the LDL receptor are hydrolyzed to produce cholesterol and an acyl chain. Cholesterol, in (urn, activates the enzyme acyl-CoA cholesterol acyl-transferase (ACAT) which re-esterifies cholesterol. In an apparently futile cycle, the cholesteryl esters are hydrolyzed by cholesteryl ester hydrolase. The cholesterol moiety has several fates it may leave the cell and bind to an acceptor such as high-density lipoprotein (HDL), it may be converted to steroid hormones, or it may be reesterified by ACAT. When the cellular cholesterol concentration falls, the activity of HMG-CoA reductase is increased, as is the number of LDL receptors, which results in an increase of cellular cholesterol, due both to de novo synthesis and to the uptake of cholesterol-rich lipoproteins in the circulation. An increase in cellular cholesterol results in the rapid decline in the mRNA levels for both HMG-CoA reductase and the LDL receptor. This coordinated regulation is brought about by the presence of an eight nucleotide sequence on the genes which code for both proteins this is termed the sterol regulatory element-1. 

---