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PubMed1994

Apparent selective bile acid malabsorption as a consequence of ileal exclusion: effects on bile acid, cholesterol, and lipoprotein metabolism.

A new model has been developed to characterise the effect of a standardised ileal exclusion on bile acid, cholesterol, and lipoprotein metabolism in humans. Twelve patients treated by colectomy and ileostomy for ulcerative colitis were studied on two occasions: firstly with a conventional ileostomy and then three months afterwards with an ileal pouch operation with an ileoanal anastomosis and a protective loop ileostomy, excluding on average 95 cm of the distal ileum. The ileostomy contents were collected during 96 hours and the excretion of bile acids and cholesterol was determined using gas chromatography-mass spectrometry. Fasting blood and duodenal bile samples were collected on two consecutive days. After the exclusion of the distal ileum, both cholic and chenodeoxycholic acid excretion in the ileostomy effluent increased four to five times without any change in cholesterol excretion. Serum concentrations of lathosterol (a marker of cholesterol biosynthesis) and 7 alpha-hydroxycholesterol (a marker for bile acid biosynthesis) were increased several fold. Plasma concentrations of total VLDL triglycerides were also increased whereas the concentrations of total and LDL cholesterol, and apolipoprotein B were decreased. There were no changes in biliary lipid composition or cholesterol saturation of bile. The results show that the exclusion of about 95 cm of distal ileum causes malabsorption of bile acids but apparently not of cholesterol. The bile acid malabsorption leads to increased synthesis of both bile acids and cholesterol in the liver. It is suggested that bile acids can regulate cholesterol synthesis by a mechanism independent of the effect of bile acids on cholesterol absorption. The enhanced demand for cholesterol also leads to a decrease in plasma LDL cholesterol and apolipoprotein B concentrations. The malabsorption of bile acids did not affect biliary lipid composition or cholesterol saturations of VLDL triglycerides.

Adult↗
PubMed1985

The regulation of steroidogenesis is different in the two types of ovine luteal cells.

Ovine luteal tissue contains two distinct steroidogenic cell types, small (8-20 microns) and large (greater than 20 microns), which differ based on morphological and biochemical criteria. Unstimulated small cells secrete low levels of progesterone, respond to LH or dibutyryl cAMP (dbcAMP) with enhanced secretion of progesterone, and contain most of the receptors for LH. The unstimulated large cells, conversely, secrete high levels of progesterone, have few, if any, receptors for LH, and do not respond to LH or dbcAMP with increased progesterone secretion. The lack of response to dbcAMP by large cells was investigated. Large cells incubated in the presence of cholesterol, ram serum, or 25-hydroxycholesterol did not demonstrate substrate limitation. Hormone-independent stimulation of adenylate cyclase by cholera toxin or forskolin resulted in increased adenylate cyclase activities (P less than 0.01), cAMP accumulation (P less than 0.05), and the binding of endogenous cAMP (P less than 0.05) by type I cAMP-dependent protein kinase in both small and large cells. These treatments were accompanied by enhanced secretion of progesterone (P less than 0.05) in small cells. In contrast, large cells did not respond with an increase in progesterone secretion under these conditions. These observations suggest that the high rate of secretion of progesterone in unstimulated large cells is not regulated by cAMP.

Animals↗
PubMed1989

Nonesterified fatty acids modulate steroidogenesis in mouse Leydig cells.

The effects of nonesterified fatty acids (NEFA) in modulating testosterone synthesis stimulated by luteinizing hormone (LH, 10 ng/sample) were investigated in isolated adult mouse Leydig cells. LH-stimulated testosterone production was inhibited by triglycerides (0-500 mg/dl, 50 mg/dl, 94% of the control and 500 mg/dl, 40%) and by a mixture of NEFA (100 microM, 70% of control, 200 microM, 54%, and greater than 200 microM, less than 50%). Oleic acid was a more potent inhibitor than linoleic, stearic, or palmitic acids. 8-Bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP, 5 mM) stimulated testosterone production comparable to LH but failed to reverse the inhibition of steroidogenesis produced by the NEFA. The inhibition produced by NEFA was dependent on extracellular Ca2+; and a Ca2+ channel antagonist, verapamil (10 microM), enhanced the inhibition of chylomicrons and fatty acids. 22(R)-hydroxycholesterol (10 microM) reversed the inhibition produced by NEFA. The inhibitory effects of NEFA were reversible by removal of the fatty acids. The results indicate that NEFA are potent modulators of testosterone synthesis in Leydig cells stimulated with either LH, cAMP, or intracellular Ca2+. NEFA inhibit steroidogenesis at one of the steps preceding conversion of cholesterol to pregnenolone.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2004

Cholesterol modulates human intestinal sodium-dependent bile acid transporter.

Bile acids are efficiently absorbed from the intestinal lumen via the ileal apical sodium-dependent bile acid transporter (ASBT). ASBT function is essential for maintenance of cholesterol homeostasis in the body. The molecular mechanisms of the direct effect of cholesterol on human ASBT function and expression are not entirely understood. The present studies were undertaken to establish a suitable in vitro experimental model to study human ASBT function and its regulation by cholesterol. Luminal membrane bile acid transport was evaluated by the measurement of sodium-dependent 3H-labeled taurocholic acid (3H-TC) uptake in human intestinal Caco-2 cell monolayers. The relative abundance of human ASBT (hASBT) mRNA was determined by real-time PCR. Transient transfection and luciferase assay techniques were employed to assess hASBT promoter activity. Caco-2 cell line was found to represent a suitable model to study hASBT function and regulation. 25-Hydroxycholesterol (25-HCH; 2.5 microg/ml for 24 h) significantly inhibited Na(+)-dependent 3H-TC uptake in Caco-2 cells. This inhibition was associated with a 50% decrease in the V(max) of the transporter with no significant changes in the apparent K(m). The inhibition in hASBT activity was associated with reduction in both the level of hASBT mRNA and its promoter activity. Our data show the inhibition of hASBT function and expression by 25-HCH in Caco-2 cells. These data provide novel evidence for the direct regulation of human ASBT function by cholesterol and suggest that this phenomenon may play a central role in cholesterol homeostasis.

Caco-2 Cells↗
PubMed2003

Identification and characterization of rodent ABCA1 in isolated type II pneumocytes.

ATP-binding cassette transporter A1 (ABCA1) promotes transfer of cholesterol and phospholipid from cells to lipid-free serum apolipoproteins. ABCA1 mRNA and protein expression in primary cultures of rodent type II cells was sensitive to upregulation with 5 microM 9-cis-retinoic acid (9cRA) and 6.2 microM 22-hydroxycholesterol (22-OH). The increase in ABCA1 protein levels was time dependent and was maximal after 16 h of exposure to 9cRA + 22-OH. Inducible ABCA1 was also found in transformed cell lines of lung origin: WI38/VA13, A549, and NIH-H441 cells. Stimulation of ABCA1 in rat type II cells by 9cRA + 22-OH resulted in a four- or fivefold enhancement of efflux of radioactive phospholipid or cholesterol, respectively, from the pneumocytes to apolipoprotein AI (apo AI), whereas cAMP (0.3 mM) had no effect. ABCA1-mediated lipid efflux to apo AI was independent of the surfactant secretion pathway, inasmuch as upregulation of ABCA1 resulted in a reduction of secretagogue-stimulated surfactant phospholipid release. These studies demonstrate the presence of functional ABCA1 in type II cells from the lung.

ATP Binding Cassette Transporter 1↗
PubMed2004

SREBP-1a polymorphism influences the risk of Alzheimer's disease in carriers of the ApoE4 allele.

Sterol regulatory element-binding proteins (SREBPs) are transcription factors involved in cholesterol and fatty acid synthesis. Recently, a polymorphism in the 5'-region of the SREBP-1a gene has been described to be correlated with alterations in the plasma levels of cholesterol. Consequently the relationship between this SREBP-1a gene polymorphism and Alzheimer's disease (AD) alone and in combination with the apolipoprotein E (ApoE) 4 allele was evaluated. No association between SREBP-1a polymorphism alone and AD could be seen. However, in the group of healthy ApoE4 allele carriers, the number of homozygote SREBP-1a DeltaG allele carriers was significantly higher than in AD patients. Cerebrospinal fluid levels of cholesterol were lower in AD patients who were carriers of the SREBP-1a DeltaG allele, and the ratio of 24S-hydroxycholesterol to cholesterol was increased in these probands. Our data suggest a reduced risk of AD in carriers of an ApoE4 allele who are additionally homozygous for the SREBP-1a DeltaG allele, which is possibly due to the influence of SREBP-1a polymorphism on brain cholesterol metabolism. This is the first report on a genetic factor which prevents the deleterious effect of the ApoE4 allele and thus reduces the risk of AD.

Aged↗
PubMed2005

Baseline oxysterols and other markers of oxidative stress, inflammation and malnutrition in the vitamin e and intima media thickness progression in end-stage renal disease (VIPER) cohort.

BACKGROUND AND OBJECTIVES: Oxysterols are markers of oxidative stress, levels of which have not yet been reported in hemodialysis (HD) patients. This study was designed to compare levels of the oxysterols 7-ketocholesterol (7KC) and 7beta-hydroxycholesterol (7betaOH) between a cohort of HD patients and healthy controls. METHODS: This nested cross-sectional study reflects baseline (pre-intervention) values for markers of oxidative stress, inflammation and nutrition status in the 160-member vitamin E and carotid intima media thickness progression in end-stage renal disease (VIPER) cohort (age 64.1 +/- 8.8, 33.5% female). Age- and sex-matched healthy volunteers served as controls. Plasma oxysterols 7KC and 7betaOH were determined by isotope dilution gas chromatography/mass spectrometry. RESULTS: Despite higher plasma alpha-tocopherol levels in HD patients than controls (36.0 +/- 9.3 vs. 31.8 +/- 8.4 micromol/l, p = 0.007), 7KC levels (9.8 +/- 6.9 vs. 5.9 +/- 2.8 nmol/mmol cholesterol, p < 0.0001) and 7betaOH levels (8.7 +/- 4.3 vs. 2.7 +/- 1.6 nmol/mmol cholesterol, p < 0.0001) were higher in HD patients. The oxysterol 7betaOH was significantly, inversely associated with prealbumin (r = -0.18, p = 0.03), though neither oxysterol was significantly associated with any other marker of oxidative stress, inflammation or nutrition status and did not discriminate for CVD in HD patients. CONCLUSIONS: Elevated levels of the oxysterols 7KC and 7betaOH indicate that HD patients are in a state of oxidative stress compared to healthy controls. However, oxysterols 7KC and 7betaOH did not appear to contribute additional information about oxidative stress among HD patients.

Adult↗
PubMed1990

Reconstructed skin from cultured human keratinocytes and fibroblasts on a collagen-glycosaminoglycan biopolymer substrate.

A lattice prepared from biopolymer substrate bovine skin collagen and chondroitin-6-sulfate (glycosaminoglycan) served as a support for normal human keratinocytes and fibroblasts. Air exposure of the lattice on an agarose block gave rise to reconstructed epidermis, the histological features of which are very similar to normal human epidermis. Indirect immunofluorescence staining of the plasma membrane-associated transglutaminase, the enzyme responsible for the synthesis of the cornified envelope, revealed the same tissue distribution as observed in vivo. Cell cycle analysis showed a large shift of the normal human keratinocyte population into S-phase and cell division during the 1st week postinoculation. Furthermore, the effects of two modulators of differentiation (25-hydroxycholesterol and sodium butyrate) on the reconstruction of the epidermis were evaluated.

Animals↗
PubMed1993

Influence of cholesterol derivatives on cytoskeletal organization of human carcinoma cells.

Recent developments of immunotherapeutic approaches have shown that artificial ordering of tumor cell membranes with cholesterol hemisuccinate (CHS) or 25-hydroxycholesterol (25-OH) may significantly enhance the immunogenicity of human renal adenocarcinoma cells. To gain further insight into the molecular mechanism of these sterols, we investigated cytoskeletal modification, which is related to the cell membrane. After treatment of human renal carcinoma cells with these cholesterol (at 10(-6) and 10(-7) M) for 5 days, we observed a disorganization of the submembrane end of the cytoplasmic actin stress fibers by cytofluorescence. The microtubule network was not affected. Thus, in the present study, we found that changes in membrane physicochemical properties impaired the anchorage of actin microfilaments in the plasma membrane of human renal cancer cells. Under the same experimental conditions, such modifications were not observed in normal cells (human fibroblasts) or in human hepatoma cells. We suggest that incubation of cancer cells with these sterols induced a redistribution of the cholesterol-rich membrane microdomains which are linked to the cytoskeleton through submembrane proteins.

Actins↗
PubMed2002

Mechanism of accumulation of cholesterol and cholestanol in tendons and the role of sterol 27-hydroxylase (CYP27A1).

OBJECTIVE: Tendon xanthomas are deposits of lipids and connective tissue commonly found in hypercholesterolemic patients. Macrophages are likely to be responsible for the lipid accumulation. Normolipidemic patients with the rare disease cerebrotendinous xanthomatosis, lacking the enzyme sterol 27-hydroxylase (CYP27A1), develop prominent xanthomas in tendons and brain containing both cholestanol and cholesterol, with a cholestanol:cholesterol ratio higher than that in the circulation. Because of its ability to convert cholesterol into polar metabolites that leave the cells faster, CYP27A1 has been suggested to be an antiatherogenic enzyme. The hypothesis was tested that tendons contain CYP27A1 that may be of importance for the normal efflux of both steroids. METHODS AND RESULTS: Western blotting and combined gas chromatography-mass spectrometry showed that human tendons contain significant amounts of CYP27A1 and its product, 27-hydroxycholesterol. Immunohistochemistry showed that CYP27A1 is present in macrophages and tenocytes. The tendons also contained cholestanol, with a cholestanol:cholesterol ratio slightly higher than that in the circulation. Recombinant human CYP27A1, and cultured human macrophages containing this enzyme, had similar activity toward cholesterol and cholestanol. After loading of macrophages with labeled cholesterol and cholestanol, there was an efflux of these steroids in both unmetabolized and 27-oxygenated form, resulting in a significant cellular accumulation of cholestanol compared with cholesterol. CONCLUSION: The results are consistent with the possibility that CYP27A1 is of importance for the efflux of both cholesterol and cholestanol from tendons.

Adult↗
PubMed2003

Lysophosphatidylcholine regulates synthesis of biglycan and the proteoglycan form of macrophage colony stimulating factor.

OBJECTIVE: We have shown that copper-oxidized LDL (Ox-LDL) regulates proteoglycan synthesis by arterial smooth muscle cells. Ox-LDL specifically upregulates biglycan expression while causing elongation of glycosaminoglycan chains on all of the major secreted proteoglycans (biglycan, decorin, and versican), resulting in enhanced lipoprotein-binding interactions. It is not known which component of Ox-LDL is responsible for these effects. This study investigated the ability of several bioactive components of Ox-LDL to regulate proteoglycan synthesis. METHODS AND RESULTS: Those tested included 2 oxysterols (7-ketocholesterol and 7beta-hydroxycholesterol) and 2 lysolipids (lysophosphatidylcholine and lysophosphatidic acid) formed during LDL oxidation. 7-ketocholesterol, lysophosphatidylcholine, and lysophosphatidic acid all increased proteoglycan MWapp, which is correlated with chain elongation and enhanced lipoprotein-binding properties in vitro. Lysophosphatidylcholine mimics the ability of Ox-LDL to stimulate biglycan expression and also causes a marked induction of the core protein for the proteoglycan form of macrophage colony stimulating factor. CONCLUSIONS: Multiple oxidized lipid molecules can modulate proteoglycan synthesis and may have important consequences to atherogenesis via processes that involve enhanced lipoprotein retention as well as the promotion of macrophage survival and differentiation.

Animals↗
PubMed2004

Brain cholesterol: long secret life behind a barrier.

Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450-generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far. In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed.

Animals↗
PubMed1995

Effect of dietary cholesterol and fat on the expression of hepatic sterol 27-hydroxylase and other hepatic cholesterol-responsive genes in baboons (Papio species).

Our studies of baboons with low and high responses to dietary cholesterol and fat suggest that low-responding baboons increase the activity of hepatic sterol 27-hydroxylase, an important enzyme of bile acid synthesis, considerably more than do high-responding baboons when challenged with a high-cholesterol, high-fat (HCHF) diet. The present studies were conducted to determine whether hepatic sterol 27-hydroxylase mRNA levels and plasma 27-hydroxycholesterol concentrations also differed with dietary responsiveness. Sixteen adult male baboons with a wide range of VLDL cholesterol plus LDL cholesterol (VLDL+LDL cholesterol) response to an HCHF diet were selected. They were examined first while on a chow diet and then after 1, 3, 6, 10, 18, 26, 36, 52, 72, and 104 weeks on the HCHF diet. Plasma and lipoprotein cholesterol concentrations increased rapidly during the first 3 weeks and stabilized thereafter. On the basis of the response in VLDL/LDL cholesterol, we selected five low-responding, four medium-responding, and five high-responding baboons for more intensive study in more detail. In low responders, the major increase in serum cholesterol concentration was in HDL cholesterol, whereas in medium and high responders it was in both VLDL+LDL and HDL cholesterol. In low and medium responders, serum or VLDL+LDL cholesterol did not change after 3 weeks of consumption of the HCHF diet, whereas in high responders VLDL+LDL cholesterol declined between 78 and 104 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Involvement of oxysterols and lysophosphatidylcholine in the oxidized LDL-induced impairment of serum albumin synthesis by HEPG2 cells.

Oxidized low density lipoproteins (Ox-LDLs) are increasingly thought to be a key element in atherogenesis. We have previously reported that serum albumin has important antioxidant properties and that a reduced synthesis of albumin may represent a crucial point in the overall antioxidant defense. In the present work, we aimed at determining whether Ox-LDL could modulate albumin synthesis in cultured human hepatocytes (HepG2 cells). With the use of enzyme immunoassay and radiolabeled leucine incorporation followed by specific immunoprecipitation, Ox-LDL was found to lead to a dose-dependent decrease in albumin secretion. Moreover, the protein synthesis and mRNA levels were decreased in the presence of Ox-LDL, as assessed by Northern blot analysis. Because oxysterols and lysophospholipids are key components of Ox-LDL, we tested the effects of oxysterols (7-ketocholesterol and 25-hydroxycholesterol) and lysophosphatidylcholine on albumin secretion and expression. In our experimental conditions, we found that incubations with oxysterols or lysophosphatidylcholine at pathophysiological concentrations similar to those measured in Ox-LDLs reproduced the above-mentioned inhibitory effects on albumin synthesis. On the basis of our in vitro data, we propose that this newly described biological effect of Ox-LDL might partly explain the findings of epidemiological studies indicating that reduced levels of serum albumin are associated with increased mortality.

Antioxidants↗
PubMed2004

Vascular endothelial growth factor activation of sterol regulatory element binding protein: a potential role in angiogenesis.

By stimulating the migration and proliferation of endothelial cells (ECs), vascular endothelial growth factor (VEGF) is a potent angiogenic factor. However, the molecular mechanism involved in the VEGF-induced angiogenesis remains elusive. We hypothesized that sterol regulatory element binding proteins (SREBPs), transcription factors governing cellular lipid homeostasis, play an important role in regulating angiogenesis in response to VEGF. VEGF activated SREBP1 and SREBP2 in ECs, as demonstrated by the increased SREBPs, their cleavage products, and the upregulation of the targeted genes. VEGF-induced SREBP activation depended on SREBP cleavage-activating protein (SCAP), because knocking down SCAP by RNA interference (RNAi) inhibited SREBP activation in response to VEGF. SREBP activation was also blocked by 25-hydroxycholesterol (25-HC). To verify the functional implication of SREBPs in VEGF-induced angiogenesis, we tested the role of SREBPs in EC migration and proliferation. SCAP RNAi or 25-HC inhibited VEGF-induced pseudopodia extension and migration of ECs. Both treatments inhibited VEGF-induced EC proliferation, with cell growth arrested at the G(0)/G(1) phase and a concomitant decrease of the S phase. Blocking the PI3K-Akt pathway inhibited the VEGF-activated SREBPs, demonstrating that PI3K-Akt regulates SREBPs. Consistent with our in vitro data, SREBP1 was detected in newly developed microvasculatures in a rabbit skin partial-thickness wound-healing model. SREBP inhibition also markedly suppressed VEGF-induced angiogenesis in chick embryos. In summary, this study identifies SREBPs as the key molecules in regulating angiogenesis in response to VEGF.

Animals↗
PubMed2004

Role for sterol regulatory element-binding protein in activation of endothelial cells by phospholipid oxidation products.

Oxidized phospholipids, including oxidation products of palmitoyl-arachidonyl-phosphatidyl choline (PAPC), are mediators of inflammation in endothelial cells (ECs) and known to induce several chemokines, including interleukin-8 (IL-8). In this study, we show that oxidized PAPC (OxPAPC), which accumulates in atherosclerotic lesions, paradoxically depletes endothelial cholesterol, causing caveolin-1 internalization from the plasma membrane to the endoplasmic reticulum and Golgi, and activates sterol regulatory element-binding protein (SREBP). Cholesterol loading reversed these effects. SREBP activation resulted in increased transcription of the low-density lipoprotein receptor, a target gene of SREBP. We also provide evidence that cholesterol depletion and SREBP activation are signals for OxPAPC induction of IL-8. Cholesterol depletion by methyl-beta-cyclodextrin induced IL-8 synthesis in a dose-dependent manner. Furthermore, cholesterol loading of ECs by either the cholesterol-cyclodextrin complex or caveolin-1 overexpression inhibited OxPAPC induction of IL-8. These observations suggest that changes in cholesterol level can modulate IL-8 synthesis in ECs. The OxPAPC induction of IL-8 was mediated through the increased binding of SREBP to the IL-8 promoter region, as revealed by mobility shift assays. Overexpression of either dominant-negative SREBP cleavage-activating protein or 25-hydroxycholesterol significantly suppressed the effect of OxPAPC on IL-8 transcription. A role for SREBP activation in atherosclerosis is suggested by the observation that EC nuclei showed strong SREBP staining in human atherosclerotic lesions. The current studies suggest a novel role for endothelial cholesterol depletion and subsequent SREBP activation in inflammatory processes in which phospholipid oxidation products accumulate.

Animals↗
PubMed2001

Bioavailability of vitamin E as function of food intake in healthy subjects: effects on plasma peroxide-scavenging activity and cholesterol-oxidation products.

Clinical trials with vitamin E have yielded contrasting results. In these trials, the amount of vitamin E given was different, and the compliance was not assessed in all studies. In addition, the modality of intake, ie, in relation to food, was not specified in any trial. Vitamin E is lipophilic, and its absorption is expected to be increased by food. We studied the bioavailability of vitamin E in relation to food intake and the effect on the lipid peroxide-scavenging activity of plasma and on 7beta-hydroxycholesterol and 7-ketocholesterol (oxysterols) as markers of oxidant stress. Twenty healthy Italian subjects were randomly assigned to take vitamin E at 300 mg/d on an empty stomach (group A) or during dinner (group B) for 15 days. Plasma vitamin E markedly increased in group B (84%) compared with group A (29%). The lipid peroxide-scavenging activity of plasma increased significantly in group B (14%, P=0.005) but did not change in group A. All subjects showed very low levels of plasma oxysterols, which were not affected by vitamin E supplementation in either group. This study shows that plasma concentration of vitamin E and plasma antioxidant activity in response to oral supplementation are markedly affected by food intake. Healthy Italian subjects show very low levels of cholesterol oxidation products; these low levels are possibly related to the Mediterranean diet. To obtain maximal absorption, vitamin E must be given at meals. These data should be taken into account in clinical trials with vitamin E.

Adult↗
PubMed1978

Identification of a lymphocyte surface receptor for low density lipoprotein inhibitor, an immunoregulatory species of normal human serum low density lipoprotein.

The present study demonstrates the existence on human peripheral blood lymphocytes of a saturable cell surface receptor for low density lipoprotein inhibitor (LDL-In), a subset of normal human serum low density lipoprotein (LDL) that has been previously demonstrated to suppress selected lymphocyte functions in vivo and in vitro. The binding of radioiodinated LDL-In of demonstrable biological activity occurs rapidly and is quantitatively augmented by prior cultivation of the lymphocytes in lipoprotein-depleted serum, suggesting regulation of receptor density by lipoproteins in vivo. Binding is temperature dependent, facilitated by calcium ions, saturable at 4 degrees C within 40-60 min, and blocked by prior exposure to unlabeled LDL-In. The lymphocyte receptor is trypsin sensitive and regenerates in vitro with a t1/2 of 3.6 h. LDL-In receptors are calculated to have a maximum density of 4,860 +/- 460 per cell if uniformly distributed on all lymphocyte subsets. These receptors have an estimated average association constant of 1.47 X 10(7) liters/mol. When considered in context of the estimated concentration of LDL-In in blood, the receptors should be partially occupied in vivo by endogenous plasma LDL-In. Prior site occupancy inhibition experiments designed to analyze the specificity of LDL-In binding demonstrate that (a) LDL-In is 13.7-fold more effective than whole LDL in blocking the subsequent binding of 125I-LDL-In to cells; and that (b) LDL is 11-fold more effective than LDL-In in blocking the binding of 125I-LKL. This is consistent with the degree of contamination of each lipoprotein with the other lipoprotein. An independent identity of the LDL-In receptor is also supported by observations that in contrast to the previously described LDL receptor, synthesis and expression of the LDL-In receptor on lymphocytes are not suppressed by cultivation of the cells in the presence of 25-hydroxycholesterol and cholesterol. These findings suggest the existence of a previously undescribed and discrete receptor on lymphocytes for LDL-In, and that the modulation of lymphocyte function by LDL-In may be mediated by a specific cell surface receptor pathway.

Cholesterol↗