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J S Parks

Publications and source records attributed to J S Parks.

At least 73 records · Page 4Linked to original sources
PubMed1995

Dietary fatty acid modification of HDL phospholipid molecular species alters lecithin: cholesterol acyltransferase reactivity in cynomolgus monkeys.

In the following report, cynomolgous monkeys, fed atherogenic diets containing either saturated, monounsaturated, polyunsaturated (n-6 Poly) or fish oil (n-3 Poly) fat as 35% of total calories, provide a model for the study of dietary fat effects on plasma lipoproteins and atherosclerosis. We have previously described the ability of polyunsaturated fat diets to lower plasma described the ability of polyunsaturated fat diets to lower plasma high density lipoprotein (HDL) cholesterol levels and alter HDL subpopulation distribution in the primate model. These experiments investigate possible mechanisms responsible for such modifications. Animals fed polyunsaturated fat had significantly lower plasma concentrations of HDL cholesterol, total plasma cholesterol, and apolipoprotein A-I. Such changes were reflected in the distribution of protein among HDL subfractions, with the most remarkable modification in subclass distribution being the preponderance of small HDL particles in the n-3 Poly-fed animals. Striking alterations were also observed in the distribution of phosphatidylcholine (PC) molecular species (diet effect P < 0.0001 for all major molecular species). Phosphatidylcholine isolated from lipoproteins were used to make recombinant HDL (rHDL) particles. The reaction rate of purified lecithin:cholesterol acyltransferase (LCAT) with particles made from n-3 Poly-derived PC was 50% of that determined using rHDL formed with PC from other dietary groups (P < 0.0001). When the distribution of LCAT-derived rHDL cholesteryl esters was analyzed, LCAT demonstrated little selectivity for certain PC molecular species except in n-3 Poly-derived rHDL where 18:2-containing PC was selectively utilized. These data demonstrate that differences in dietary fat intake can significantly alter HDL PC concentration and molecular species distribution. We suggest that diet-induced alterations in HDL PC molecular species modify the type of cholesteryl esters produced during the LCAT reaction thereby affecting the plasma cholesteryl ester pool. We also propose that dietary n-3 Poly affects cholesteryl ester metabolism in part via LCAT by lowering PC (LCAT substrate) availability, altering the rate of the LCAT reaction, and decreasing HDL cholesterol concentrations; however, n-6 Poly dietary fat effects on HDL concentration appear to be through some mechanism other than LCAT.

Animals↗
PubMed1995

Effect of apolipoprotein A-I deficiency on lecithin:cholesterol acyltransferase activation in mouse plasma.

Plasma cholesteryl ester (CE) synthesis by lecithin cholesterol acyltransferase (LCAT) is activated by apolipoprotein (apo)A-I. We studied the effect of plasma apoA-I concentration on LCAT activation, using normal, heterozygous or homozygous apoA-I-deficient mice made by gene targeting. Plasma esterified cholesterol concentrations of mice fed chow diets were ordered (mean +/- SEM): 105 +/- 7 (normal) > 70 +/- 5 (heterozygotes) > 26 +/- 2 (homozygotes) mg/dl. Plasma free cholesterol concentrations were similar among the three genotypes. Endogenous LCAT activity, measured as the decrease in plasma free cholesterol after a 1 h incubation at 37 degrees C, was ordered: 44 +/- 3 (normal) > 21 +/- 2 (heterozygotes) > 5 +/- 1 (homozygotes) nmol CE formed/h per ml plasma. Using a recombinant exogenous substrate consisting of egg yolk phospholipid, [14C]cholesterol, and apoA-I, CE formation of normals and heterozygotes was similar (27.4 +/- 0.6 and 28.8 +/- 1.3 nmol/h per ml plasma, respectively), but was significantly less for homozygotes (19.2 +/- 1.7 nmol/h per ml plasma). However, using a small unilamellar vesicle substrate particle containing phospholipid and [14C]cholesterol, CE formation was ordered: 1.6 +/- 0.1 (normal) = 1.6 +/- 0.1 (heterozygotes) > 0.6 +/- 0.1 (homozygotes) nmol/h per ml plasma; addition of apoA-I to the plasma of homozygous animals restored CE formation to normal levels (1.6 +/- 0.1). CE fatty acid analysis demonstrated that plasma from homozygous mice contained significantly more saturated and monounsaturated and fewer polyunsaturated fatty acids compared to normal and heterozygous mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Dietary polyunsaturated fat decreases interaction between low density lipoproteins and arterial proteoglycans.

Polyunsaturated dietary fat (n-3 and n-6) results in less atherosclerosis in monkeys compared to lard (Parks, J.S., Kaduck-Sawyer, J., Bullock, B.C., and Rudel, L.L., Arteriosclerosis 10, 1102-1112; Rudel, L.L., Parks, J.S., Johnson, F.L., and Babiak, J., J. Lipid Res. 27, 465-474, 1986). We hypothesized that this was due, in part, to a decreased reactivity of low density lipoproteins (LDL) with arterial proteoglycans (PG). To test this hypothesis, cynomolgus monkeys were fed diets containing lard, safflower oil (n-6 polyunsaturated; Poly), menhanden fish oil (FO), or oleic acid-rich safflower oil (oleinate; Mono) for 14 mon, and plasma LDL were isolated and characterized. Several properties of LDL thought to be important in the interaction of LDL with arterial PG were measured including LDL particle size, chemical composition, sialic acid content, density distribution, apolipoprotein E (apoE) content and cholesteryl ester transition temperature. Plasma LDL cholesterol concentrations (mg/dL) after 14 mon of diet consumption averaged (mean +/- SEM): FO (366 +/- 45), Lard (352 +/- 27), Poly (279 +/- 24), and Mono (230 +/- 43). The composition of LDL was similar among diet groups except that FO LDL were relatively depleted of cholesteryl ester and enriched in protein and were smaller in size. LDL sialic acid content was similar among diet groups (4.5-5.0 micrograms/mg LDL protein). The LDL apoE/B molar ratio, a measure of the apoE content per LDL particle averaged: Mono (3.0 +/- 1.0), Poly (2.0 +/- 0.1), Lard (1.8 +/- 0.5), and FO (1.0 +/- 0.2).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Cytokines decrease apolipoprotein accumulation in medium from Hep G2 cells.

Cytokines, important biochemical mediators of inflammation, cause a rapid fall in the plasma concentration of cholesterol in vivo. One mechanism by which cytokines may cause acquired hypocholesterolemia is by decreasing the hepatic synthesis and secretion of apolipoproteins. To test this hypothesis, we incubated Hep G2 cells with human recombinant tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6. Each of the cytokines resulted in a dose-related reduction in the concentrations of apolipoprotein (apo) A-I, apoB, and lecithin:cholesterol acyltransferase (LCAT) activity in the medium after 24 hours of incubation. The effect of cytokines on apolipoprotein accumulation was not affected by preincubation of Hep G2 cells with fatty acids. Cytokines decreased the concentration of cellular apoA-I mRNA in a dose-related fashion but did not affect cellular concentrations of apoB mRNA. The concentrations of triglyceride and cholesterol were also reduced in the medium of cells incubated with cytokines. Total cell sterol synthesis rates were calculated by [14C]acetate incorporation. Cells incubated with interleukin-6 had a 31% increase in sterol synthesis rate but a 41% decrease in sterol secretion. These data suggest that these cytokines can decrease the hepatic synthesis and/or secretion of apolipoproteins and that this may explain, in part, the acquired hypocholesterolemia seen during acute and chronic inflammation.

Apolipoprotein A-I↗
PubMed1994

Impaired growth in Rabson-Mendenhall syndrome: lack of effect of growth hormone and insulin-like growth factor-I.

Mutations in the insulin receptor gene cause the severe insulin-resistant syndromes leprechaunism and Rabson-Mendenhall syndrome. There is no accepted therapy for these inherited conditions. Here we report the results of recombinant human GH (rhGH) and recombinant human insulin-like growth factor-I (rhIGF-I) treatment of a male patient, Atl-2, with Rabson-Mendenhall syndrome. The patient was small for gestational age, had premature dentition, absence of sc fat, acanthosis nigricans, fasting hypoglycemia and postprandial hyperglycemia, and extremely high concentrations of circulating insulin (up to 8500 microU/mL). Fibroblasts and lymphoblasts established from this patient had reduced insulin binding, which was 20-30% of the control value. Binding of epidermal growth factor, IGF-I, and GH to the patient's fibroblasts was normal. The growth of fibroblasts cultured from patient Atl-2 in vitro was intermediate between that of fibroblasts from patients with leprechaunism and control values. The patient's growth curve in vivo was far below the fifth percentile despite adequate nutrition. To stimulate growth, therapy with rhGH was initiated, the rationale being to stimulate hepatic IGF-I production and IGF-I receptor signaling, and bypass the inherited block in insulin receptor signaling. Therapy with rhGH (up to 0.5 mg/kg.week) did not improve growth and failed to increase the levels of circulating IGF-I and IGF-binding protein-3 over a 14-month period. As rhGH could not stimulate growth, rhIGF-I (up to 100 micrograms/kg.day) was given by daily sc injection. No increase in growth velocity was observed over a 14-month period. These results indicate that both GH and IGF-I fail to correct growth in a patient with severe inherited insulin resistance. The lack of efficacy of IGF-I treatment may be related to multiple factors, such as the poor metabolic state of the patient, the deficiency of serum carrier protein for IGF-I, an increased clearance of the growth factor, IGF-I resistance in target cells at a receptor or postreceptor level, or an inhibitory action of the mutant insulin receptors on IGF-I receptor signaling.

Acanthosis Nigricans↗
PubMed1994

Dietary fish oil-induced decrease in low density lipoprotein binding to fibroblasts is mediated by apolipoprotein E.

In a previous study we demonstrated that isocaloric substitution of fish oil (FO) for lard in the diet of cynomolgus monkeys resulted in low density lipoproteins (LDL) that were poorer competitors for binding of a standard 125I-labeled LDL and led to less cholesteryl ester accumulation in skin fibroblasts (Linga, V., et al. 1993. J. Lipid Res. 34: 769-778). The decreased binding and cholesteryl ester accumulation by FO LDL appeared related to the LDL apolipoprotein E (apoE) content. We hypothesized that FO LDL had reduced binding to skin fibroblasts due to a decrease in receptor active apoE. To test this hypothesis and determine the relative contribution of apoE versus apolipoprotein B (apoB) in binding of LDL to skin fibroblasts, LDL from cynomolgus monkeys fed lard or FO-containing diets were isolated, characterized, radioiodinated, and tested for binding in the absence or presence of a 10-fold molar excess of monoclonal antibody to the receptor binding domain of apoE (1D7) or apoB-100 (MB47). FO LDL were smaller, contained less apoE (E/B molar ratio = 0.48 +/- 0.03 vs. 1.85 +/- 0.22; P < 0.001), and had a weaker binding affinity (Kd = 11.3 +/- 1.6 vs. 3.8 +/- 0.80 microgram/ml; P < 0.01) compared to the lard counterparts. Furthermore, the apoE/B molar ratio of LDL appeared inversely related to the Kd for binding to skin fibroblasts. Incubation of LDL with skin fibroblasts in the presence of a 10-fold molar excess of monoclonal antibody directed at the receptor binding domain of apoB-100 (MB47) eliminated 96 +/- 3% of binding of FO LDL, but eliminated only 43 +/- 18% of binding for lard LDL. Incubation with a 10-fold molar excess of monoclonal antibody to the receptor-binding domain of apoE (1D7) eliminated only 23 +/- 6% of FO LDL binding to fibroblasts relative to a no-antibody control, but for lard LDL 44 +/- 11% of binding to fibroblasts was eliminated. Both antibodies together blocked all binding of LDL from both diet groups. In a fluid phase precipitation assay > 75% of the LDL particles from both diet groups was precipitated with saturating amounts of MB47, indicating that the proportion of LDL particles expressing this epitope was the same for both diet groups. The same assay using 1D7 showed approximately 4-fold greater precipitation of LDL in the lard versus FO group.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Preservation of somatostatin secretion in cystic fibrosis patients with diabetes.

Immunohistochemical studies of pancreatic tissue from patients with cystic fibrosis associated with diabetes mellitus (CFDM) show increased numbers of somatostatin secreting delta cells. To look for a possible functional correlate to this finding basal and arginine stimulated plasma somatostatin and serum C peptide concentrations in eight insulin treated patients with cystic fibrosis and eight normal male controls were measured. Mean basal somatostatin concentrations were not different in the two groups. Mean peak somatostatin concentrations were significantly higher in the group with CFDM: 11.60 pmol/l v 7.14 pmol/l in controls. Mean peak C peptide concentrations were significantly lower in the group with cystic fibrosis: 0.89 nmol/l v 4.27 nmol/l in controls. This observation provides a physiological correlate to the pathological finding of increased somatostatin content in pancreatic tissue from patients with CFDM. Selective preservation of somatostatin secretion in patients with cystic fibrosis may further complicate pancreatic endocrine insufficiencies through paracrine inhibition of insulin and glucagon secretion.

Adult↗
PubMed1993

Genetics of growth hormone gene expression.

The regulation of pituitary GH gene expression depends on binding of transcriptional activation proteins to cis-active DNA sequences preceding the GH-1 gene. The POU homeodomain protein Pit-1 is found in the nuclei of somatotrophs, lactotrophs and thyrotrophs. It fosters differentiation of these pituitary cell types and is required for hormone production by mature cells. In theory, defects in GH secretion can be caused by mutations in the GH-1 promoter sequence or in the gene encoding Pit-1. In the former case, deficiency would be limited to GH, and in the latter deficiencies extend to prolactin (Prl) and thyrotropin (TSH) as well as to GH. Both the Pit-1 gene and the GH-1 gene have been examined in children with extreme growth failure. Studies of kindreds with GH, Prl and TSH deficiency have disclosed a variety of mutations in the Pit-1 gene. These include nonsense mutations, missense mutations that diminish binding and transcriptional activation, and also mutations that appear to increase promoter binding while eliminating transcriptional activation. This latter class of mutation exerts a dominant negative effect in vivo as well as in vitro. There are many examples of deletions in the GH-1 coding sequence. Some are very large and cause the loss of GH-1, chorionic somatomammotropin and placental GH genes. Others are very small, involving only 1 or 2 bases. They produce frameshifts and premature stop signals. All types produce complete deficiency of GH, but antibody development during treatment has proven to be quite variable. The cDNA for the GH-releasing hormone receptor has recently been cloned and sequenced.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Childhood consumption of dietary polyunsaturated fat lowers risk for coronary artery atherosclerosis in African green monkeys.

This study was designed to test the hypothesis that consumption of diets enriched in polyunsaturated fatty acids beginning at birth and continuing into young adulthood would lower the risk for atherosclerotic coronary heart disease early in life through their effects on plasma lipid and apolipoprotein concentrations while supporting good health and normal development. Accordingly, African green monkeys (n = 140) were raised on atherogenic diets (0.8 mg cholesterol per kcal) enriched with either saturated or n-6 polyunsaturated fatty acids. Breast milk from mothers fed the polyunsaturated fat diet became enriched in polyunsaturated fatty acids relative to the saturated group; thus, the period of nursing also reflected the dietary fatty acid shift. Age, gender, and dietary fat type independently affected plasma lipid and apolipoprotein concentrations. Age effects were similar for all lipid and lipoprotein variables; the concentrations were low immediately after birth, increased dramatically during the first 4-6 months of life, and then attained levels similar to those of adult animals by 2 years of age. Significant differences by gender were found such that females maintained lower total plasma cholesterol concentrations and higher high density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I concentrations. Dietary fat effects were age dependent. Before weaning at 5 months of age, total plasma cholesterol and apoB concentrations were lower in animals consuming polyunsaturated fat, and this pattern was maintained into young adulthood. Lower concentrations of plasma triglycerides, HDL cholesterol, and apoA-I for polyunsaturated fat-fed animals were found only in the postweaning period (6-60 months of age). Since this pattern of response to dietary polyunsaturated fat in the juvenile animals was similar to that for adult animals fed these same diets in which there was less atherosclerosis and because subsequent studies have documented less coronary artery atherosclerosis in the polyunsaturated fat-fed juveniles, we conclude that early dietary intervention was beneficial in this group for lowering the risk of coronary artery atherosclerosis. The results in this primate model support the concept that intervention to modify coronary heart disease risk that is initiated early in childhood will have beneficial effects.

Aging↗
PubMed1993

Characterization of a noncontiguous gene deletion of the growth hormone receptor in Laron's syndrome.

Noncontiguous deletion of the GH receptor (GHR) gene has been described as a molecular defect causing Laron's syndrome (LS). The abnormal allele (GHR Del-3,5,6) lacks exons 3, 5, and 6. Exon 4 is retained on variant-sized restriction fragments. We studied DNA from 10 additional LS subjects of Jewish-oriental origin and found this allele in 3 samples. All subjects with this complex deletion allele were from Iran or Iraq and were not clinically distinguishable from other individuals with LS. Multiple restriction enzyme digests and Southern blotting with GHR exon 4-specific probes demonstrated that the allele retains genomic material for at least 9.8 kilobases 5' and 1.8 kilobases 3' to exon 4. Reverse transcription of mRNA, polymerase chain reaction amplification, and cDNA sequencing showed that exon 4 is syntenic and colinear with the other GHR exons. Normal splice sites were used, but the predicted protein was severely truncated due to a frameshift and a premature stop codon in exon 7. The premature stop codon terminated the protein after amino acid 53 and led to loss of the transmembrane and intracellular portions of the receptor. This mutant GHR gene results clinically in severe GH insensitivity.

Alleles↗
PubMed1993

Interrelationships of alpha-tocopherol with plasma lipoproteins in African green monkeys: effects of dietary fats.

The distributions of plasma lipoprotein alpha-tocopherol and lipids were studied in African green monkeys consuming diets enriched in saturated, monounsaturated, or polyunsaturated fatty acids. Plasma total alpha-tocopherol concentrations were not different among the animals fed the three diets, whereas plasma total cholesterol concentrations were significantly different among the diet groups. The alpha-tocopherol: total lipid molar ratio in plasma high density lipoproteins (HDL) was significantly higher compared to low density lipoproteins (LDL) and very low plus intermediate-sized low density lipoprotein (VLDL + ILDL) of each diet group, suggesting that HDL may exhibit a greater affinity for alpha-tocopherol. The presence of a positive correlation between HDL alpha-tocopherol and plasma apoA-I concentration and the absence of a correlation between HDL alpha-tocopherol and total lipid in HDL suggested that alpha-tocopherol associates with the protein moiety of HDL on the surface of the particle. A direct relationship between the plasma apoA-I: apoB molar ratio and the percentage of alpha-tocopherol found in the HDL fraction indicated that a greater proportion of alpha-tocopherol associates with HDL as the number of HDL particles in plasma increases relative to LDL particles. LDL from monkeys fed diets high in saturated fat contained 40% and 33% fewer alpha-tocopherol molecules per particle than LDL from monkeys fed polyunsaturated and monounsaturated fats, respectively. The phase transition temperature of LDL cholesteryl esters, indicative of the physical state of the lipids in the particle core, was well above body temperature in LDL from saturated fat-fed monkeys and was significantly higher compared to the other diet groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Lipoprotein lipase enhances the interaction of low density lipoproteins with artery-derived extracellular matrix proteoglycans.

The association of plasma low density lipoproteins (LDL) with arterial proteoglycans (PG) is of key importance in LDL retention and modification in the artery wall. Lipoprotein lipase (LpL), the rate-limiting enzyme for hydrolysis of lipoprotein triglyceride, is known to bind both LDL and arterial PG. In the presence of LpL, cellular internalization and degradation of LDL is enhanced by a pathway initiated by interaction of LDL with a cell surface heparan sulfate proteoglycan. To determine whether LpL enhances the binding of LDL to arterial chondroitin sulfate (CS)PG and dermatan sulfate (DS)PG, the major extracellular PG of the artery wall, a microtiter plate assay was used to study LpL-PG-LDL interactions. Binding of LDL to both CSPG and DSPG was increased in the presence of LpL but differential effects were seen for the two PG. LpL enhanced the binding of LDL to CSPG a maximum of 20% and to DSPG a maximum of 40%. Heparin displacement of PG binding suggested a greater binding strength for DSPG-LpL-LDL with 0.25 micrograms heparin required to displace 50% of DSPG compared to 0.01 micrograms to displace 50% of CSPG. The greater enhancement of DSPG-LDL interaction by LpL is of particular interest since increases in DSPG correlate with the accumulation of aortic cholesterol. These data suggest that lipoprotein lipase may enhance the interaction of plasma low density lipoprotein with arterial chondroitin sulfate proteoglycan and dermatan sulfate proteoglycan and thus facilitate low density lipoprotein retention in the artery wall.

Animals↗
PubMed1993

Dietary fish oil modification of cynomolgus monkey low density lipoproteins results in decreased binding and cholesteryl ester accumulation by cultured fibroblasts.

Dietary fish oil (FO) has been reported to increase low density lipoprotein (LDL) receptor function resulting in lower plasma LDL concentrations in the rat (Ventura et al. J. Clin. Invest. 84: 528-537, 1989). The purpose of this study was to determine whether dietary FO, as compared to lard, affected the receptor-mediated uptake of LDL by cultured skin fibroblasts. Plasma LDL was isolated by combined ultracentrifugation and column chromatography from cynomolgus monkeys fed diets enriched in FO or lard and the effect of these two dietary fats on the binding of LDL and esterified cholesterol (EC) accumulation by cultured fibroblasts was determined. There was no difference in total plasma or LDL cholesterol concentrations between diet groups. The monkeys fed FO had significantly smaller LDL which, on average, contained less protein, phospholipid (PL), and free and esterified cholesterol compared to the LDL from monkeys fed the lard diet. FO LDL were less effective than lard LDL in competing for binding, internalization, and degradation of a standard 125I-labeled LDL by fibroblasts (11.0 +/- 2.4 vs. 3.0 +/- 0.8 micrograms LDL protein/ml for 50% displacement of binding, respectively; P = 0.013). FO versus lard LDL also resulted in less accumulation of cellular EC after a 24-h incubation with fibroblasts (7.7 +/- 0.2 vs. 13.0 +/- 0.4 micrograms EC/mg protein, respectively; P = 0.0001). In general, cellular EC accumulation was proportional to LDL particle size and LDL apoE/B molar ratio; however, LDL from the lard group resulted in greater EC accumulation even when LDL particle size and apoE content were nearly equivalent between diet groups. When LDL were isolated from the same animals by sequential ultracentrifugation, the lard LDL apoE was reduced 22% compared to column isolated LDL and this resulted in a 32% decrease in cellular EC accumulation. However, for FO LDL, apoE content was reduced 34% by sequential ultracentrifugation but this only resulted in a 10% decrease in EC accumulation. These results suggested that lard LDL contained more receptor-active apoE than FO LDL. We conclude that isocaloric substitution of fish oil for lard in the diet of cynomolgus monkeys results in LDL particles that bind less avidly to LDL receptors and in less EC accumulation in fibroblasts. The decreased binding of LDL from the FO group appears related to their decreased size and CE content as well as the decreased content of receptor-active apoE relative to the lard group.

Animals↗
PubMed1993

Decreased binding of apoA-I to phosphatidylcholine monolayers containing 22:6 n-3 in the sn-2 position.

Previous studies have shown that dietary fish oil can modify the distribution and fatty acyl composition of plasma phospholipids. Although it is known that the type of phospholipid can affect the binding of apolipoprotein A-I (apoA-I), little is known about the effect of n-3 fatty acid enrichment in phospholipids on apoA-I binding. We hypothesize that phosphatidylcholine (PC) surfaces containing n-3 fatty acids at the sn-2 position bind apoA-I less avidly than those containing sn-2 18:1. PC species containing sn-1 16:0 and sn-2 18:1 (POPC), sn-2 20:5 n-3 (PEPC), or sn-2 22:6 n-3 (PDPC) were used in apoA-I monolayer binding studies. The molecular surface area at any given surface pressure (tau) was ordered: PDPC > PEPC > POPC and at tau = 25 mN/m the molecular surface areas were 86.2, 78.8 and 72 A 2/molecule, respectively. Binding of [14C]apoA-I (radiolabeled by reductive methylation) to PDPC at tau i = 15 mN/m was less than that for POPC whether expressed as nmol A-I/m2 surface or molecules A-I/1000 PC. The apparent Kd for steady state apoA-I binding to PEPC (2.1 nM) and PDPC (2.2 nM) was greater than that for POPC (1.2 nM); the maximum binding capacity (nmol/m2) was ordered PEPC (9.4) > POPC (8.1) > PDPC (6.7). Similar results were found when a fixed amount of apoA-I was injected beneath the PC monolayers equilibrated at different initial surface pressures. The calculated surface area available for bound apoA-I was 15, 17, and 23 A 2/amino acid for POPC, PEPC, and PDPC at tau i = 15 mN/m, respectively. We conclude that the binding affinity of apoA-I for PDPC and PEPC is less than that for POPC and that apoA-I bound to PDPC is more loosely folded than that to POPC. These studies suggest that the type of sn-2 fatty acid can influence apoA-I binding to PC.

Apolipoprotein A-I↗
PubMed1992

Effect of interleukin-1 alpha on lipoprotein lipids in cynomolgus monkeys: comparison to tumor necrosis factor.

Acute inflammation is associated with changes in lipoprotein metabolism. Cytokines are thought to mediate the metabolic effects of the inflammatory process. This study was undertaken to compare the effects of interleukin-1 alpha (IL-1 alpha) to tumor necrosis factor (TNF) on lipoprotein metabolism in non-human primates. Recombinant human IL-1 alpha (100 micrograms/kg), TNF alpha (20 micrograms/kg) and lipopolysaccharide (20 micrograms/kg) were injected into cynomolgus monkeys. Lipoprotein concentrations, plasma activities of post-heparin lipase (PHLA) and lecithin:cholesterol acyltransferase (LCAT) were measured prior to and 24 and 48 h after, injection. All three injections caused afebrile response in the animals. Interleukin-1 alpha had no effect on plasma lipoprotein concentrations, composition of lipoproteins or enzyme activity. In contrast, injection of TNF caused significant changes in lipoprotein concentrations. There was a 38% increase in plasma triacylglycerol and 30% decrease in plasma cholesterol at 48 h after injection. Concentrations of apolipoproteins A-I and B were decreased 20% and 44%, respectively, at 48 h. Compositional analyses of lipoprotein particles after TNF injection showed that both the LDL and HDL particles had decreased content of cholesterol ester and increased triacylglycerol after injection, and plasma activities of PHLA and LCAT were decreased. These changes were qualitatively similar to those seen after LPS injection. These data suggest that, unlike TNF, IL-1 alpha is not an important mediator of the inflammatory process on lipoprotein metabolism in cynomolgus monkeys.

Animals↗
PubMed1992

Mutation of the POU-specific domain of Pit-1 and hypopituitarism without pituitary hypoplasia.

A point mutation in the POU-specific portion of the human gene that encodes the tissue-specific POU-domain transcription factor, Pit-1, results in hypopituitarism, with deficiencies of growth hormone, prolactin, and thyroid-stimulating hormone. In two unrelated Dutch families, a mutation in Pit-1 that altered an alanine in the first putative alpha helix of the POU-specific domain to proline was observed. This mutation generated a protein capable of binding to DNA response elements but unable to effectively activate its known target genes, growth hormone and prolactin. The phenotype of the affected individuals suggests that the mutant Pit-1 protein is competent to initiate other programs of gene activation required for normal proliferation of somatotrope, lactotrope, and thyrotrope cell types. Thus, a mutation in the POU-specific domain of Pit-1 has a selective effect on a subset of Pit-1 target genes.

Animals↗
PubMed1992

Hepatic ACAT activity in African green monkeys is highly correlated to plasma LDL cholesteryl ester enrichment and coronary artery atherosclerosis.

Previous studies and this study of African green monkeys show a strong positive correlation between plasma low density lipoprotein (LDL) size and the extent of coronary artery atherosclerosis (CAA). Increased LDL size was principally due to the accumulation of cholesteryl oleate molecules within the particle core, suggesting that many of these cholesteryl esters were of tissue origin, i.e., from the acyl-coenzyme A:cholesterol acyltransferase (ACAT) reaction instead of the lecithin:cholesterol acyl-transferase (LCAT) reaction. The current study was conducted to test the hypothesis that ACAT in the liver is the source of the increased numbers of cholesteryl oleate molecules in plasma LDL particles that appear to increase the atherogenic potential of LDL. Monkeys were fed diets rich in fat (lard, safflower oil, or fish oil) and cholesterol for 3-6 years before liver perfusion, ACAT assay, and evaluation of CAA. Hepatic ACAT activity was positively correlated with hepatic cholesteryl ester secretion (r = 0.61, p < 0.001), plasma LDL cholesteryl ester content (r = 0.60, p < 0.0001), and the extent of CAA (r = 0.62, p < 0.0001). The number of cholesteryl oleate molecules within LDL increased proportionally with LDL size in each of the diet groups. Hepatic cholesteryl oleate concentration was correlated with the accumulation of cholesteryl oleate in liver perfusate (r = 0.72, p < 0.01) and with plasma LDL cholesterol oleate content (r = 0.73, p < 0.0001). Our interpretation is that these data, obtained in a relevant primate model of CAA, suggest that hepatic ACAT increases the atherogenicity of LDL by augmenting both the secretion by the liver and accumulation in plasma LDL of cholesteryl oleate.

Animals↗