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J S Parks

Publications and source records attributed to J S Parks.

At least 19 recordsLinked to original sources
PubMed1996

Optic nerve hypoplasia: absence of posterior pituitary bright signal on magnetic resonance imaging correlates with diabetes insipidus.

PURPOSE: Magnetic resonance imaging has been used to examine children with optic nerve hypoplasia for pituitary abnormalities who may be at risk for anterior pituitary hormonal deficiencies. We correlated the sellar and optic pathway anatomic findings on magnetic resonance imaging in children with optic nerve hypoplasia with findings from their endocrinologic and ophthalmologic examinations to determine whether magnetic resonance imaging findings predict anterior and posterior pituitary dysfunction. METHODS: A retrospective review identified five children with optic nerve hypoplasia and endocrinopathy who also underwent high resolution volumetric magnetic resonance imaging. RESULTS: All children had severe bilateral optic nerve hypoplasia and anterior pituitary hormone deficiencies. Three children had no recognizable intrasellar or ectopic posterior pituitary bright spot on magnetic resonance imaging; all had clinical evidence of diabetes insipidus. Two patients with a recognizable but ectopic posterior pituitary did not have diabetes insipidus. CONCLUSION: Children with optic nerve hypoplasia and no recognizable posterior lobe of the pituitary gland on magnetic resonance imaging are at risk for both anterior and posterior pituitary dysfunction, whereas those with a posterior lobe on magnetic resonance imaging appear to have intact posterior pituitary function.

Diabetes Insipidus↗
PubMed1996

Glycosylation structure and enzyme activity of lecithin:cholesterol acyltransferase from human plasma, HepG2 cells, and baculoviral and Chinese hamster ovary cell expression systems.

The glycosylation state of lecithin:cholesterol acyltransferase (LCAT) may be important in determining its enzymatic activity. We compared glycosylation structure, enzyme kinetics, and phosphatidylcholine (PC) acyl specificity of human LCAT from four sources: human plasma (pLCAT), media from HepG2 cells (HepG2 LCAT), media from SF21 cells infected with a recombinant baculovirus (bLCAT) and media from stably transfected Chinese hamster ovary (CHO) cells (CHO LCAT). bLCAT was underglycosylated (molecular weight approximately 50 kDa) and resistant to digestion by N-glycanase F, endoglycosidase F, and neuraminidase. CHO and HepG2 LCAT were overglycosylated (approximately 68 kDa and approximately 70-75 kDa) compared to pLCAT (approximately 65 kDa). CHO LCAT, like pLCAT, was sensitive to N-glycanase F and neuraminidase but not to endoglycosidase F. HepG2 LCAT demonstrated resistance to N-glycanase F and endoglycosidase F. Apparent Km values for all four enzymes were similar (1.4-9.2 microM cholesterol) for recombinant high density lipoproteins (rHDL) containing sn-1 16:0, sn-2 18:1 PC (POPC). Apparent Vmax values (nmol cholesteryl ester formed/h per micrograms) were 52.6 for pLCAT, 48.6 for CHO LCAT, 15.3 for bLCAT, and 8.3 for HepG2 LCAT. Changes in PC acyl specificity in the presence and absence of cholesterol were characterized by comparing the ratio of LCAT activity on rHDL containing sn-1 16:0, sn-2 20:4 PC (PAPC) or POPC (PAPC/POPC activity ratio). The ratios for pLCAT, bLCAT, CHO LCAT, and HepG2 LCAT activity were 0.63, 0.49, 0.56, and 0.51 with cholesterol and 0.34, 0.29, 0.36, and 0.99 without cholesterol, respectively. We conclude that LCAT source influences glycosylation structure, which affects the apparent Vmax for cholesteryl ester formation with only minor changes in apparent Km or acyl substrate specificity.

Amidohydrolases↗
PubMed1996

High level secretion of wild-type and mutant forms of human proapoA-I using baculovirus-mediated Sf-9 cell expression.

To facilitate the investigation of apoA-I structure:function relationships as they relate to LCAT activation and lipid binding, we have developed an apoA-I baculoviral expression and purification system that yields milligram quantities of wild-type or mutant proapoA-I. Baculovirus-infected Sf-9 cells, grown in suspension, were found to secrete high levels of human wild-type (40-50 mg/l) or mutant apoA-I protein (1-38 mg/l), which was determined to be > 95% pure following a two-step purification procedure. In the case of wild-type apoA-I, ELISA showed that approximately 13-18% of the total protein secreted into the culture medium was apoA-I. To isolate pure protein from culture medium, 72 h post-infection medium was subjected to preparative reverse phase high performance liquid chromatography (HPLC), followed by DEAE ion-exchange chromatography. Purity and molecular size determination of wild-type proapoA-I protein was verified by SDS polyacrylamide gel electrophoresis, electrospray mass spectrometry, and N-terminal sequencing. In addition, recombinant discoidal apoA-I:phospholipid complexes prepared from wild-type or plasma apoA-I showed similar particle size and LCAT activation properties. To fully characterize the utility of this expression system, the expression levels of various mutant apoA-I proteins were compared to wild-type. Despite a lower production level seen with selected apoA-I mutants, milligram quantities of these purified mutant proteins were also obtained. In summary, we show that baculovirus-derived wild-type proapoA-I shows properties similar to plasma apoA-I relative to recombinant HDL formation, LCAT reactivity, and alpha-helical content. In addition, we show that a variety of mutant forms of human proapoA-I can be expressed and purified in abundant quantity from baculoviral-infected Sf-9 cells.

Animals↗
PubMed1996

Low density lipoprotein particle size and core cholesteryl ester physical state affect the proton NMR magnetic environment of fatty acid methylene and methyl nuclei.

Recent studies using proton NMR to quantify plasma lipoprotein concentrations have shown that lipoprotein particle size affects the chemical shift of methyl and methylene resonances. The purpose of this study was to investigate the interrelationship of low density lipoprotein (LDL) size and cholesteryl ester (CE) physical state on the chemical shift of methyl and methylene protons. LDL were isolated from the plasma of nonhuman primates fed diets containing lard or fish oil to result in a wide range of LDL particle sizes and CE core transition temperatures for NMR analysis. The proportion of nuclei in the fluid state in LDL at different temperatures, measured as proton NMR peak intensity, paralleled the melting profile of LDL CE determined by differential scanning calorimetry. At 37 degrees C the linewidths of several resolvable fatty acyl resonances, but not the choline methyl resonance, were significantly less in the fish oil LDL, indicating a less restrictive environment along the fatty acyl chain. The (CH2)n and t-CH3 resonances demonstrated an upfield shift (i.e., smaller chemical shift) with increasing temperature for both diet groups, but the peaks for fish oil LDL were always upfield from those of the lard LDL regardless of temperature. No change in the chemical shift of the choline CH3 resonance was observed as a function of dietary fat or temperature. Above the transition temperature for LDL CE there was a significant positive correlation between LDL size and the chemical shift of the (CH2)n and t-CH3 resonances. This relationship was not statistically significant for the same LDL below the Ce transition temperature. We conclude that LDL CE must be fully melted to obtain accurate results for LDL particle size distribution as well as mass quantification using portion NMR spectroscopy.

Animals↗
PubMed1996

Plasma cholesteryl ester transfer activity is modulated by the phase transition of the lipoprotein core.

Previous studies have shown that lipid transfer protein (LTP) activity is strongly temperature dependent, demonstrating a dramatic rise in activity near 37 degrees C. We have investigated the origin of this rapid rise in LTP activity. LTP-mediated transfers of radiolabeled cholesteryl ester (CE) from LDL to HDL, HDL to LDL, LDL to biotin-LDL, HDL to biotin-HDL, and between liposomes were determined as a function of assay temperature. Only assays containing LDL demonstrated this rapid rise in CE transfer activity. In contrast, TG transfer was almost linear with assay temperature. As human LDL CE undergoes a thermal phase transition near 37 degrees C, we investigated whether the rapid rise in CE transfer was dependent on this transition. Monkey LDL were isolated from animals consuming diets containing cholesterol and enriched in saturated, monounsaturated, or polyunsaturated fatty acids. With these LDL as substrate, the CE transfer between 21 degrees and 49 degrees C could be described by two straight lines, the intersection of which defined the inflection temperature. Among eight LDL samples, the inflection temperature was highly correlated with the CE phase transition determined by differential scanning calorimetry (r2 = 0.86). Both calorimetry and CE transfer activity inflection values were correlated with the saturated + monoene/polyene ratio of the LDL cholesteryl esters (r2 = 0.733 and 0.612, respectively). For LDL with inflection temperatures below 37 degrees C, CE transfer activity at 37 degrees C increased 10-14% for each 1 degree C decrease in the inflection temperature. We conclude that LTP activity is markedly affected by the physical state of the core CE. Diets rich in saturated fatty acids may result in LDL that are poor LTP substrates, which may hinder LTP's ability to promote normal lipoprotein remodeling.

Animals↗
PubMed1995

Dietary polyunsaturated fat modifies low-density lipoproteins and reduces atherosclerosis of nonhuman primates with high and low diet responsiveness.

We tested the hypothesis that an increased content of n-6 polyunsaturated fatty acids (principally linoleic acid) in an atherogenic diet of nonhuman primates would decrease atherosclerosis by modifying the composition and decreasing the concentration of plasma low-density lipoprotein (LDL). A species readily susceptible to diet-induced atherosclerosis (cynomolgus monkey) was compared with a less-susceptible species (African green monkey) with dietary cholesterol concentration and saturated or polyunsaturated fat (40% of energy) as variables. In both species, cholesterol concentrations in whole plasma, LDL, and high-density lipoprotein (HDL) were 20-30% lower when polyunsaturated fat was fed, whereas dietary cholesterol increased LDL cholesterol three- to fourfold. LDL was enriched in cholesteryl oleate when saturated fat and cholesterol were fed. Dietary linoleic acid prevented cholesteryl oleate enrichment and promoted cholesteryl linoleate accumulation in LDL. At the same plasma cholesterol concentration, cynomolgus monkeys had higher LDL cholesterol and lower HDL-cholesterol concentrations than did African green monkeys. LDL particle size was significantly (P < 0.001) larger in the group of cynomolgus monkeys fed polyunsaturated fat but tended to be smaller in African green monkeys fed polyunsaturated fat. Dietary polyunsaturated fat protected against coronary artery atherosclerosis in both species. Thus, LDL particle size, per se, was not atherogenic; instead, coronary artery atherosclerosis and cholesteryl oleate enrichment of LDL were more highly correlated. This outcome suggests that information about LDL composition may be more important for understanding the pathogenesis of atherosclerosis than previously suspected.

Animals↗
PubMed1995

Compared with dietary monounsaturated and saturated fat, polyunsaturated fat protects African green monkeys from coronary artery atherosclerosis.

Atherogenic diets enriched in saturated, n-6 polyunsaturated, and monounsaturated fatty acids were fed to African green monkeys for 5 years to define effects on plasma lipoproteins and coronary artery atherosclerosis. The monkeys fed polyunsaturated and monounsaturated fat had similar plasma concentrations of LDL cholesterol, and these values were significantly lower than for LDL in the animals fed saturated fat. Plasma HDL cholesterol concentrations were comparable in animals fed saturated and monounsaturated fat and were significantly higher than in animals fed polyunsaturated fat. Thus, the monounsaturated fat group had the lowest LDL/HDL ratio. LDL particle size was largest in the saturated and monounsaturated fat groups, significantly larger than in the polyunsaturated fat group. LDL particle enrichment with cholesteryl oleate was the greatest in the animals fed monounsaturated fat, next greatest in the saturated fat-fed animals, and was least in the polyunsaturated fat-fed animals. Coronary artery atherosclerosis as measured by intimal area was less in the polyunsaturated fat compared with the saturated fat groups, was less in the animals fed polyunsaturated fat compared with the monounsaturated fat-fed animals, but did not differ between the monounsaturated and saturated fat groups. Cholesteryl ester, particularly cholesteryl oleate, accumulation in the coronary arteries was also similar between groups fed monounsaturated and saturated fat but was minimal in the animals fed polyunsaturated fat. In sum, the monkeys fed monounsaturated fat developed equivalent amounts of coronary artery atherosclerosis as those fed saturated fat, but monkeys fed polyunsaturated fat developed less. The beneficial effects of the lower LDL and higher HDL in the animals fed monounsaturated fat apparently were offset by the atherogenic shifts in LDL particle composition. Dietary polyunsaturated fat appears to result in the least amount of coronary artery atherosclerosis because it prevents cholesteryl oleate accumulation in LDL and the coronary arteries in these primates.

Animals↗
PubMed1995

ACAT inhibitors CL 283,546 and CL 283,796 reduce LDL cholesterol without affecting cholesterol absorption in African green monkeys.

Previous studies with a number of selective acylcoenzyme A:cholesterol acyltransferase (ACAT) inhibitors in several animal models have demonstrated significant reductions in plasma cholesterol and, in some studies, triglyceride levels. This study was conducted to examine the effects of two ACAT inhibitors, CL 283,546 and CL 283,796, in cholesterol-high fat diet fed African green monkeys, a relevant primate model of hyperlipidemia and coronary artery atherosclerosis. Treatment with CL 283,546 or CL 283,796 resulted in significant reductions (ca. 25-30%) in total plasma cholesterol at both 10 and 30 mg/kg per day doses. This reduction in plasma cholesterol was due almost entirely to reduction in low density lipoprotein (LDL) cholesterol (ca. 45%) without significantly affecting high density lipoprotein (HDL) cholesterol, very low density lipoprotein + intermediate density lipoprotein (VLDL + IDL) cholesterol, or triglyceride concentrations. There were no significant effects on plasma concentrations of apolipoproteins A-I, E, or B and, thus, the reduction seen in LDL cholesterol appears to be due to a diminished cholesterol content of LDL particles. Our studies revealed that treatment with these compounds did not reduce cholesterol absorption, which was somewhat surprising as ACAT inhibitors are generally thought to exert their hypolipidemic effects, at least in part, by inhibition of intestinal cholesterol absorption. Our data are consistent with a principal activity of these drugs on the liver to reduce cholesteryl ester secretion in VLDL, leading to a diminished LDL-cholesterol content, and, presumably, enhanced biliary cholesterol-bile acid excretion.

Animals↗
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↗