Lipoproteins chemically modified

M. Lucarelli, M. Gennarelli, P. Cardelli, G. Novelli, S. Scarpa, B. Dallapiccola and R. Strom, Expression of receptors for native and chemically modified low-density lipoproteins in brain microvessels, FEBS Lett. 401 (1997) 53-58. 

Some cells have been observed to change the coding properties of newly synthesized mRNA molecules. In this process, called RNA editing, certain bases are chemically modified, deleted, or added. For example, the mRNA for apolipoprotein B-100 in liver cells codes for a 4563 amino acid polypeptide which is a component of very low density lipoprotein (VLDL). Intestinal cells produce a shorter version of the molecule called apolipoprotein B-48 (2153 amino acid residues) that becomes incorporated into the chylomicron particles produced by these cells. The cytosine in a CAA codon that specifies glutamine is converted by a deamination reaction into a uracil. The new codon, UAA, is a stop signal in translation hence a truncated polypeptide is produced during translation of the edited mRNA. 

Chemically modified lipoprotein Macrophage Modified LDL Charge- modified apo-B Not regulated Potential role in foam cell production in atherogenesis... 

The j8-VLDL receptor has been identified on mouse peritoneal macrophages [13,14], foam cells associated with rabbit aortic atherosclerotic plaques [58], and human monocyte-derived macrophages [14]. Although )8-VLDL can bind to LDL receptors, LDL do not compete with I-labeled jS-VLDL for uptake by mouse peritoneal macrophages [13,14], In addition, monocytes from LDL receptor-negative FH patients or from normal subjects express equivalent numbers of j8-VLDL receptors [14]. The j8-VLDL receptors thus are distinct from LDL receptors. The -VLDL receptor is also distinct from the receptors for chemically modified lipoproteins (see below). 

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. 

Although in vivo a proportion of foam cells in lesions are demonstrated by immunohistochemical marking to be of smooth muscle cell origin, feeding smooth muscle cells in vitro with P-very low-density lipoprotein or chemically modified LDL does not, in contrast to the case with macrophages, lead to foam cell formation (Heinecke etal. 1991, Hoff et al. 1991, Huff et al. 1991). The reason for this differences in response relates in the types and properties of the hpoprotein receptors expressed in cultured macrophages and cultured smooth muscle cells. Smooth muscle cells, like fibroblasts (the cell type on which the classical studies were conducted), are typical LDL receptor cells (Goldstein and Brown 1977). 

New insights into the analysis of hydrophobically post-translational modified proteins could be achieved by the construction of lipidated proteins in a combination of bioorganic synthesis of activated lipopeptides and bacterial expression of the protein backbone (Fig. 19). The physico-chemical properties of such artificial lipoproteins differ substantially from those of the corresponding lipopeptides. The pronounced dominance of the hydrophilic protein moiety (e.g., for the Ras protein 181 amino acids) over a short lipopeptide with one or two hydrophobic modifications provides solubility up to 10 4 mol/1, while the biotinylated or fluorescence labeled lipopeptides exhibit low solubility in aqueous solutions and can be applied in the biophysical experiments only in vesicle integrated form or dissolved in organic solvent. 

Cellular components in atherosclerotic plaques include foam cells, which are transformed macrophages, and smooth muscle cells filled with cholesteryl esters. These cellular alterations result from endocytosis of modified lipoproteins via at least four species of scavenger receptors. Chemical modification of lipoproteins by free radicals creates ligands for... 

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