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Lipoprotein receptors are membrane proteins which play a central role in lipid metabolism. Although cells are capable of synthetizing de novo cholesterol from acetate, cholesterol is mostly of food origin or synthetized by the liver. The liver is the only organ which can catabolize the cholesterol and clear it from the circulation into biliary acids. Cholesterol, triglycerides and phospholipids are carried in the blood and in the interstitial fluid in association with specific proteins called apolipoproteins (apo), and form the lipoproteins. Although lipoproteins can be separated by their physico-chemical properties (i.e. density), they are the result of continuous exchanges of lipids and apolipoproteins. Lipoproteins are secreted by the intestine and the liver. Enterocytes and hepatocytes associate, in their endoplasmic reticulum, apolipoproteins and lipids from dietary intake and/or endogenous synthesis to form chylomicrons (intestine) or Very Low Density Lipoproteins (VLDL, in the liver). Lipolysis by the lipases of the triglycerides leads to fatty acids which are delivered to cells by a non-receptor pathway. On the contrary, the delivery of cholesterol to cells is dependent of receptors which recognize the lipoproteins by their protein moiety. Peripheric cells use cholesterol from the Low Density Lipoproteins (LDL, final product of VLDL intravascular catabolism) by the LDL receptor pathway. By this receptor, hepatocytes can also perform the clearance of LDL from the organism. The LDL receptor, or B/E receptor, can recognize lipoproteins by both apo B or apo E. However, other receptors might exist to explain the normal catabolism of apo E- containing lipoproteins in patients genetically deficient in LDL receptor. One of the most characterized candidate protein for chylomicrons receptor is the LRP (LDL receptor Related Protein) which shares a strong homology with some domains of the LDL receptor, and which is shown to be the alpha 2-macroglobulin receptor previously described. Due to the delay in clearance by the liver, LDL can undergo oxidation. Oxidized LDL are not recognized by LDL receptor but rather "scavenger" receptors in macrophages and vascular endothelial smooth muscle cells. This metabolism leads to the formation of atherosclerotic plaques. High Density Lipoproteins (HDL) are implicated in the removal of excess cholesterol from peripheral cells and the transport to the liver. Specific HDL binding sites to several mammalian cells have been shown by numerous investigators and one candidate protein has been cloned. Analysis of HDL-induced signal transduction has been a very active field of research.(ABSTRACT TRUNCATED AT 400 WORDS)
Cell Mol Biol (Noisy-le-grand) 1994 Jun
PMID:Lipoprotein receptors. 806 63

To determine whether the sarcolemmal-free cholesterol content influences the tolerance to anoxia in cultured neonatal rat cardiomyocytes, we modulated the free cholesterol content of the cultures, and determined the time course of anoxia-induced cell death. Incubation for 5 h with liposomes having a free cholesterol to phospholipid molar ratio of 2, 0.5 and 0, resulted in a change of cellular free cholesterol content by +54.7 +/- 5.8% (P < 0.001), by -5.2 +/- 6.3% (n.s.), and by -22.1 +/- 4.9% (P < 0.01), respectively, when compared to cultures incubated without liposomes (control). In cells which were loaded with cholesterol, it was verified that the extra cholesterol was transferred predominantly to the sarcolemma, which was associated with a decrease in sarcolemmal fluidity. In cells which underwent cholesterol reduction it was verified that free cholesterol was retracted selectively from the sarcolemma, associated with an increase in sarcolemmal fluidity. Cellular enrichment with free cholesterol caused a delay of anoxia-induced release of lactate dehydrogenase (LDH): the time at which half-maximal release of LDH was reached (LDH50%) occurred later by 35.5 +/- 3.4 min (P < 0.001) compared to anoxic control cultures. Cholesterol reduction diminished the tolerance to anoxia: LDH50% occurred earlier by 36.4 +/- 7.8 min (P < 0.01), compared to anoxic control cultures. Cultures which were incubated with liposomes having a free cholesterol to phospholipid molar ratio of 0.5 had unchanged sarcolemmal free cholesterol content, unchanged sarcolemmal fluidity, and an unchanged LDH50% during anoxia in comparison to control cultures, excluding any effect of the incubation with liposomes per se. The present study indicates that the sarcolemmal free cholesterol content of cardiomyocytes is a determinant of their tolerance to anoxia.
J Mol Cell Cardiol 1994 May
PMID:The effect of sarcolemmal cholesterol content on the tolerance to anoxia in cardiomyocyte cultures. 807 18

We administered ethanol to pregnant rats and determined cholesterol, lipid phosphorus and fluorescence anisotropy of diphenylhexatriene (DPH) and of trimethylaminophenyl hexatriene (TMA-DPH) in erythrocyte ghosts of newborn pups and of their mothers. Cholesterol content was different in dams and pups and changed after treatment. Age, but not ethanol, affected lipid phosphorus. Either age (dams versus pups) or treatment affected the curves of DPH fluorescence anisotropy (r) versus temperature (T), but those of TMA-DPH did not change, indicating that only the inner core of the membrane was influenced. We conclude that adult and erythrocyte ghosts differed for the lipid composition, for the dependence of r on T (for DPH) and for the effects of ethanol dosing on these parameters.
Biochem Mol Biol Int 1994 May
PMID:The effect of maternal ethanol intoxication on erythrocyte ghost fluidity in new-born rat pups. 808 Nov 99

Cholesterol biosynthesis and uptake are controlled by a classic end product-feedback mechanism whereby elevated cellular sterol levels suppress transcription of the genes encoding 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase, HMG-CoA reductase, and the low-density lipoprotein receptor. The 5'-flanking region of each gene contains a common cis-acting element, designated the sterol regulatory element (SRE), that is required for transcriptional regulation. In this report, we describe mutant Chinese hamster ovary (CHO) cell lines that lack SRE-dependent transcription. Mutant cell lines were isolated on the basis of their ability to survive treatment with amphotericin B, a polyene antibiotic that kills cells by interacting with cholesterol in the plasma membrane. Four mutant lines (SRD-6A, -B, -C, and -D) were found to be cholesterol auxotrophs and demonstrated constitutively low levels of mRNA for all three sterol-regulated genes even under conditions of sterol deprivation. The mutant cell lines were found to be genetically recessive, and all four lines belonged to the same complementation group. When transfected with a plasmid containing a sterol-regulated promoter fused to a bacterial reporter gene, SRD-6B cells demonstrated constitutively low levels of transcription, in contrast to wild-type CHO cells, which increased transcription under conditions of sterol deprivation. Mutation of the SREs in this plasmid prior to transfection reduced the level of expression in wild-type CHO cells deprived of sterols to the level of expression found in SRD-6B cells. The defect in SRD-6 cells is limited to transcriptional regulation, since posttranscriptional mechanisms of sterol-mediated regulation were intact: the cells retained the ability to posttranscriptionally suppress HMG-CoA reductase activity and to stimulate acyl-CoA:cholesterol acyltransferase activity. These results suggest that SRD-6 cells lack a factor required for SRE-dependent transcriptional activation. We contrast these cells with a previously isolated oxysterol-resistant cell line (SRD-2) that lacks a factor required for SRE-dependent transcriptional suppression and propose a model for the role of these genetically defined factors in sterol-mediated transcriptional regulation.
Mol Cell Biol 1993 Sep
PMID:Loss of transcriptional activation of three sterol-regulated genes in mutant hamster cells. 810 88

Cholesterol 7 alpha-hydroxylase (7 alpha-hydroxylase) is the rate-limiting enzyme in bile acid biosynthesis. It is subject to a feedback control, whereby high levels of bile acids suppress its activity, and cholesterol exerts a positive control. It has been suggested that posttranscriptional control plays a major part in that regulation. We have studied the mechanisms by which cholesterol and bile acids regulate expression of the 7 alpha-hydroxylase gene and found it to be solely at the transcriptional level by using two different approaches. First, using a tissue culture system, we localized a liver-specific enhancer located 7 kb upstream of the transcriptional initiation site. We also showed that low-density lipoprotein mediates transcriptional activation of chimeric genes, containing either the 7 alpha-hydroxylase or the albumin enhancer in front of the 7 alpha-hydroxylase proximal promoter, to the same extent as the in vivo cholesterol-mediated regulation of 7 alpha-hydroxylase mRNA. In a second approach, using transgenic mice, we have found that expression of an albumin enhancer-7 alpha-hydroxylase-lacZ fusion gene is restricted to the liver and is regulated by cholesterol and bile acids in a manner quantitatively similar to that of the endogenous gene. We also found, that a liver-specific enhancer is necessary for expression of the rat 7 alpha-hydroxylase gene, in agreement with the tissue culture experiments. Together, these results demonstrate that cholesterol and bile acids regulate the expression of the 7 alpha-hydroxylase gene solely at the transcriptional level.
Mol Cell Biol 1994 Apr
PMID:Cholesterol and bile acids regulate cholesterol 7 alpha-hydroxylase expression at the transcriptional level in culture and in transgenic mice. 813 78

We have studied the expression of apolipoprotein E (ApoE) mRNA in the cerebella of control and experimental rabbits fed with a cholesterol-rich diet for 8 weeks. Cholesterol-treated rabbits show a dramatic increase in serum cholesterol levels; however, no significant variations in the expression level of cerebellar ApoE mRNA were found in comparison to control rabbits. In addition, no differences were observed between control and hypercholesterolemic rabbits in the in situ hybridization pattern of ApoE mRNA on cerebellar cortex sections. ApoE mRNA was localized in astroglial processes associated with Purkinje cell bodies and dendrites, granule cell clusters, blood vessels and nerve fibers of the white matter. No expression of ApoE mRNA was observed in Purkinje and granule cell neurons. Polarized light examination of cryostat cerebellar sections revealed the absence of cholesterol-rich microglia/macrophage cells induced by the hypercholesterolemia. In this way, neither reactive microglial cells nor perivascular phagocytes were found by ultrastructural analysis in hypercholesterolemic conditions. The pattern of glial fibrillary acidic protein of the astroglial cells of the cerebellar cortex as well as their nuclear size were unchanged following cholesterol treatment, indicating the absence of astroglial activation induced by hypercholesterolemia. Our results suggest that cerebellar ApoE does not contribute to the general cholesterol homeostasis outside of the brain and supports the view that this cerebellar ApoE is involved in paracrine and autocrine functions particularly related with synapse turnover and membrane remodelling of astroglial cells.
Brain Res Mol Brain Res 1994 Jan
PMID:Apolipoprotein E expression in the cerebellum of normal and hypercholesterolemic rabbits. 816 12

Axenic strains of Blastocystis hominis incorporated 32P, added to the medium as orthophosphate, into a number of phospholipids, including sphingomyelin, cardiolipin, phosphatidic acid, the phosphoglycerides of choline, ethanolamine, serine, and inositol and some other minor phospholipids. Radioactive palmitate and glycerol provided in the growth medium introduced radiolabel into diacylglycerols, triacylglycerols, and all major phosphoglycerides found in the organism. Palmitate is a major fatty acid of cholesterol esters in B. hominis, but radioactive palmitate did not enter the cholesterol ester pool. Radioactive acetate was not incorporated into any lipids. Cholesterol and cholesterol esters of the organism were not labeled when cells were grown in the presence of radioactive glucose, mevalonic acid, or mevalonolactone. Radioactive cholesterol added to the medium became stably associated with B. hominis cells, but none of the radioactive cholesterol entered the cholesterol ester pool. Cholesterol-[3H]-palmitate added to the medium became stably associated with the organism, and most of the radioactivity associated with the cells remained in the cholesterol ester fraction on extended incubation. These results show that this parasitic protozoan has the capacity to synthesize most cellular lipids de novo, but suggest that it acquires free cholesterol and intact cholesterol esters directly from growth medium.
Comp Biochem Physiol Biochem Mol Biol 1994 Apr
PMID:Lipid biosynthesis by axenic strains of Blastocystis hominis. 820 79

In eukaryotic cells oxysterols inhibit cholesterol biosynthesis and cell growth. A potent oxysterol, 25-hydroxycholesterol, was used to investigate the biological effects of oxysterols on three clonal lines of either glucocorticoid-sensitive or -resistant CEM cells, human leukemic T-lymphocytes. In addition, the glucocorticoid sensitivity of an oxysterol-resistant CEM cell line was tested. Oxysterols blocked growth and caused the lysis of cells regardless of their glucocorticoid response. All cells studied herein possessed an oxysterol binding protein with high affinity for 25-hydroxycholesterol. For all clones grown in serum-free medium, the half-maximal cytolytic concentration of 25-hydroxycholesterol (20-40 nM) correlated with its affinity (Kd = approximately 31 nM) for this oxysterol binding protein. Both cholesterol and mevalonate reversed 25-hydroxycholesterol cytotoxicity; 3-6 microM cholesterol or 0.1 mM mevalonate decreased 60 nM 25-hydroxycholesterol cytotoxicity by 50%. This cholesterol or mevalonate reversal appeared possible even after several days of 60 nM oxysterol treatment. The protective effect of cholesterol could be overcome by increasing 25-hydroxycholesterol concentrations. Cholesterol and mevalonate did not prevent glucocorticoid-mediated lymphocytolysis. Furthermore, the oxysterol-resistant line was sensitive to dexamethasone lysis. These data support the hypothesis that oxysterols and glucocorticoids act independently to block the growth of human leukemic lymphoblasts.
J Steroid Biochem Mol Biol 1993 Oct
PMID:Oxysterol-induced cell death in human leukemic T-cells correlates with oxysterol binding protein occupancy and is independent of glucocorticoid-induced apoptosis. 821 73

The death of a cell results in a large amount of membrane lipid, predominantly phospholipids and cholesterol, that must be eliminated. In this study, we have examined what happens to phospholipids in dying rat platelets. Rat platelets were incubated for up to three days following their activation with thrombin. Platelet death occurred during the first day of incubation. This was indicated by a complete loss of platelet lactate dehydrogenase into the incubation medium. The platelets progressively lost over one-half of their phospholipid content during the three days of incubation. Cholesterol and sphingomyelin (the phospholipid with the highest affinity for cholesterol) were not lost during the same period. Our findings suggest that significant degradation of cellular non-sphingomyelin phospholipid can be triggered by cell death. The preservation of sphingomyelin in dying platelets, may be an adaptive response to maintain cholesterol in a solubilized state within dying cells.
Virchows Arch B Cell Pathol Incl Mol Pathol 1993
PMID:Phospholipid loss in dying platelets. 828 20

Much of the oxidative damage to human LDL in vivo may lead to only minimal changes in the chemical properties of the LDL. Therefore, chemical changes were evaluated during the initial 3 hours of oxidative attack on human LDL with 5 microM Cu. HPLC analyses were calibrated with a conjugated-diene internal standard. Cholesterol-linoleate-hydroperoxide (Chol-18:2-OOH) accumulated much more rapidly than alpha-tocopherol was lost. Although large amounts of cholesterol arachidonate were destroyed, diene-containing oxidation products of this lipid were not identified by HPLC analysis. Phosphatidyl-choline-hydroperoxides accumulated much more slowly than chol-18:2-OOH. beta-carotene was oxidized relatively slowly, but lycopene was destroyed almost as fast as alpha-tocopherol. The preferential accumulation of chol-18:2-OOH is consistent with a model in which alpha-tocopherol is localized to the surface of the LDL particle, providing minimal protection to hydrophobic components in the core of the LDL.
Biochem Mol Biol Int 1993 Nov
PMID:Chemical changes during the early phase of in vitro oxidative damage to human LDL. 829 6


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