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Richard J Deckelbaum

Publications and source records attributed to Richard J Deckelbaum.

17 recordsLinked to original sources
PubMed2003

Free fatty acids modulate intermembrane trafficking of cholesterol by increasing lipid mobilities: novel 13C NMR analyses of free cholesterol partitioning.

Cholesterol and free fatty acids in membranes modulate major biological processes, and their cellular metabolism and actions are often coordinately regulated. However, effects of free fatty acid on cholesterol-membrane interactions have proven difficult to monitor in real time in intact systems. We developed a novel (13)C NMR method to assess effects of free fatty acids on molecular interactions of cholesterol within--and transfer between--model membranes. An important advantage of this method is the ability to acquire kinetic data without separation of donor and acceptor membranes. Large unilamellar phospholipid vesicles (LUV) with phosphatidylcholine/cholesterol ratios of 4:1 served as cholesterol donors. Small unilamellar vesicles (SUV) made with phosphatidylcholine were acceptors. The (13)C(4)-cholesterol peak is narrow in SUV, but very broad in LUV, spectra; the increase in intensity of this peak over time monitored transfer. Oleic acid and other long chain free fatty acids [saturated (C12-18) and unsaturated (C18)] dose-dependently increased mobilities of lipids in LUV (phospholipid and cholesterol) and cholesterol transfer rates, whereas short (C8-10) and very long (C24) chain free fatty acids did not. Decreasing pH from 7.4 to 6.5 (+/-oleic acid) had no effect on cholesterol transfer, and 5 mol % fatty acyl-CoAs increased transfer rates, demonstrating greater importance of the fatty-acyl tail over the headgroup. In LUV containing sphingomyelin, transfer rates decreased, but the presence of oleic acid increased transfer 1.3-fold. These results demonstrate free fatty acid-facilitated cholesterol movement within and between membranes, which may contribute to their multiple biological effects.

Biological Transport↗
PubMed2003

Giardiasis.

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Animals↗
PubMed2003

Enhanced bridging function and augmented monocyte adhesion by lipoprotein lipase N9: insights into increased risk of coronary artery disease in N9 carriers.

Lipoprotein lipase (LPL) is central to triacylglycerol (TG) metabolism, having both hydrolytic and bridging functions. The common LPL gene variant D9N is associated with raised TG, reduced HDL-cholesterol concentrations and increased risk of coronary artery disease (CAD). To investigate the functional basis for the phenotype in N9 carriers, CHO K1 cells were stably transfected with wild type (D9) or mutant (N9) LPL cDNA. LPL RNA expression levels, monomer-to-dimer ratios, and dimer specific activities were similar in D9 and N9 cells. Significantly enhanced binding (4.6-fold) and internalisation (2.6-fold) of 125I-LDL by N9 compared with D9 cells was eradicated by pre-treatment with either heparin or heparinase, confirming involvement of LPL and cell surface proteoglycans. N9 cells bound and internalised 3.8- and 4.4-fold more oxidised 125I-LDL, respectively, than D9 cells (both P<0.0001). Binding of monocytes was 7-fold greater to plates coated with purified LPL-N9 dimer compared with LPL-D9 (P<=0.005). Thus once on the cell surface, LPL-N9 enhances bridging, as assessed both by LDL binding and internalisation, and monocyte adhesion. This augmented LPL-N9 bridging provides a mechanism for the reported increased CAD risk in N9 carriers.

Base Sequence↗
PubMed2003

Fasting plasma insulin modulates lipid levels and particle sizes in 2- to 3-year-old children.

OBJECTIVE: Obesity and hyperinsulinemia are associated with dyslipidemia in adults and older children, but little is known about these relationships in very young children. We examined the relation of fasting insulin to lipid levels and lipid particle size in young healthy children. RESEARCH METHODS AND PROCEDURES: Analyses were performed on data from 491 healthy 2- and 3-year old Hispanic children enrolled in a dietary study conducted in New York City, 1992-1995. Obesity measures included BMI, ponderal index, skinfold thickness, and waist circumference. Low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol particle size were measured by nuclear magnetic resonance. RESULTS: Fasting insulin level was positively correlated with triglyceride levels (r = 0.24 for boys and r = 0.23 for girls; p < 0.001 for both) and inversely correlated with HDL-cholesterol level in boys (r = -0.20; p < 0.01). Higher fasting insulin level was also correlated with smaller mean HDL particle size in both boys (r = -0.21; p < 0.001) and girls (r = -0.14; p < 0.05) and smaller mean LDL particle size in boys (r = -0.13; p < 0.05). The associations of fasting insulin level with triglyceride and HDL-cholesterol levels and HDL and LDL particle size remained significant after multivariate regression adjustment for age, sex, and BMI or ponderal index. DISCUSSION: Fasting insulin level is associated with relative dyslipidemia in healthy 2- and 3-year-old Hispanic children.

Body Mass Index↗
PubMed2003

Obesity, fasting plasma insulin, and C-reactive protein levels in healthy children.

OBJECTIVE: Obesity is associated with hyperinsulinemia and increased level of C-reactive protein in older children and adults, but little is known about these relationships in very young children. We examined these relationships in healthy 2- to 3-year-old children. RESEARCH METHODS AND PROCEDURES: Analyses were performed on data from 491 healthy 2- to 3-year-old Hispanic children enrolled in a dietary study conducted in New York City, 1992 to 1995. RESULTS: Body mass index (BMI), ponderal index, and sum of four skinfolds were highly correlated (r > 0.75) in both boys and girls. Fasting insulin and glucose levels were only modestly correlated (r = 0.37 for boys and r = 0.28 for girls; p < 0.001 for both), but essentially all of the variability in a calculated index of insulin resistance was attributable to variability in fasting insulin level. The correlations of BMI with fasting insulin level were r = 0.16 (p < 0.05) in boys and r = 0.14 (p < 0.05) in girls. In separate multivariate regression analyses adjusting for age and sex, BMI and ponderal index were associated with fasting plasma insulin level (p < 0.001 for both obesity measures). In multivariate regression analyses adjusting simultaneously for age, sex, and either BMI or ponderal index, fasting insulin level, but not these obesity measures, was associated with C-reactive protein level. DISCUSSION: Obesity is associated with higher fasting insulin level, and fasting insulin is associated with C-reactive protein level, in healthy 2- to 3-year-old children.

Blood Glucose↗
PubMed2003

Physical fitness and C-reactive protein level in children and young adults: the Columbia University BioMarkers Study.

OBJECTIVE: To examine the association of physical fitness with C-reactive protein (CRP) level in children and young adults. METHODS: Subjects (N = 205) aged 6 to 24 years were enrolled in the Columbia University BioMarkers Study (1994-1998). Physical fitness was assessed using a non-effort-dependent treadmill testing protocol (physical work capacity at heart rate of 170 beats per minute). CRP level was measured using a high-sensitivity assay. RESULTS: Subjects were 54% female and 65% of Hispanic origin. Mean fitness level was higher in boys than in girls, but CRP levels did not differ by gender. Fitness level was inversely correlated with CRP (r = -0.22). This relationship was significant in boys (r = -0.32) but not in girls (r = -0.15). After multivariate regression adjustment for age, race/ethnicity, body mass index, and family history of early-onset ischemic heart disease, physical fitness remained inversely associated with CRP level in boys (beta = -0.02; standard error = 0.01). CONCLUSIONS: These findings indicate that physical fitness is inversely related to CRP level in children and that this relationship is more pronounced in boys than in girls.

Adolescent↗
PubMed2002

Apolipoprotein E and lipoprotein lipase increase triglyceride-rich particle binding but decrease particle penetration in arterial wall.

OBJECTIVE: Liver-derived apolipoprotein E (apoE) decreases atherosclerosis without altering the circulating concentrations of plasma lipoproteins. We evaluated the effects of apoE and lipoprotein lipase (LpL) on the interactions of triglyceride-rich particles (TGRPs) in the arterial wall. METHODS AND RESULTS: Quantitative fluorescence microscopy was used to study the interactions of TGRPs (25- to 35-nm diameter) in the arterial wall. Carotid arteries were harvested from rats, placed in a perfusion chamber, and perfused with fluorescently labeled TGRPs. In the absence of apoE or LpL, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine-TGRP (100 microg neutral lipid/mL) was poorly retained in the arterial wall. The addition of either apoE (10 microg/mL) or LpL (10 microg/mL) increased TGRP accumulation 220% and 100%, respectively. This effect was attenuated by heparin (10.0 IU/mL). Histological analyses of cross sections from these vessels demonstrate that in the absence of apoE or LpL, there is deep penetration of lipid into the arterial wall. With the addition of either apoE or LpL, arterial wall penetration of TGRP is blocked. CONCLUSIONS: These results demonstrate that although apoE and LpL increase arterial wall accumulation of TGRPs, these proteins also reduce the penetration of TGRPs into the arterial wall. We postulate that this may represent a novel antiatherogenic property of apoE and LpL.

Animals↗
PubMed2002

Selective uptake from LDL is stimulated by unsaturated fatty acids and modulated by cholesterol content in the plasma membrane: role of plasma membrane composition in regulating non-SR-BI-mediated selective lipid transfer.

We previously reported that unsaturated fatty acids stimulated low-density lipoprotein (LDL) particle uptake in J774 macrophages by increasing LDL receptor activity. Since free fatty acids (FFA) also change plasma membrane properties, a putative cholesteryl ester (CE) acceptor for selective uptake (SU), we questioned the ability of FFA to modulate SU from LDL. Using [(3)H]cholesteryl ether/(125)I-LDL to trace CE core and whole particle uptake, we found that oleic acid and eicosapentaenoic acid, but not saturated stearic acid, increased SU by 30% over control levels. An ACAT inhibitor, Dup128, abolished FFA effects on SU, indicating that increased SU by FFA was secondary to changes in cell-free cholesterol (FC). Consistent with these observations, ACAT inhibition increased cell FC and reduced LDL SU by half. The important role of plasma membrane composition was further demonstrated in that beta-cyclodextrin- (beta-CD-) mediated FC removal from the plasma membrane increased SU from LDL and was further stimulated by U18666A, a compound that inhibits FC transport between lysosomes and the plasma membrane. In contrast, cholesterol-saturated beta-CD markedly reduced LDL SU. In contrast to LDL SU, oleic acid, ACAT inhibition, U18666A, or beta-CD had no effects on HDL SU. Moreover, HDL SU was inhibited by antimouse SR-BI antibody by more than 50% but had little effect on LDL SU. In C57BL/6 mice fed a high fat diet, plasma FFA levels increased, and SU accounted for an almost 4-fold increased proportion of total cholesterol delivery to the arterial wall. Taken together, these data suggest that LDL SU is mediated by pathways independent of SR-BI and is influenced by plasma membrane FC content. Moreover, in conditions where elevated plasma FFA occur, SU from LDL can be an important mechanism for cholesterol delivery in vivo.

Androstenes↗
PubMed2002

Omega-3 triglycerides modify blood clearance and tissue targeting pathways of lipid emulsions.

Omega-3-rich (n-3) triglycerides (TG) are increasingly recognized as having modulating roles in many physiological and pathological conditions. We questioned whether the catabolism of lipid emulsions would be changed after enrichment with fish oil (n-3) TG as compared to enrichment with omega-6-rich soy oil (n-6) TG. Phospholipid-stabilized emulsions of n-3 TG and n-6 TG were labeled with [(3)H]cholesteryl oleoyl ether and administered by bolus injection to wild-type (WT) mice, mice lacking the low-density lipoprotein receptor (LDL-R) (LDL-R -/-), and apolipoprotein E (apoE) knockout mice (apoE -/-). The effects of exogenous apoE, heparin, Triton WR 1339, and lactoferrin on catabolism of emulsions were also assayed. n-3 TG emulsions were cleared faster from blood and had different extrahepatic tissue targeting compared to n-6 TG emulsions. In apoE -/- and LDL-R -/- mice, blood clearance of n-6 TG emulsions slowed with decreased liver uptake, but no changes were observed in n-3 TG emulsion clearance and tissue uptake compared to WT mice. In WT mice, addition of exogenous apoE to the emulsion increased liver uptake of n-6 TG emulsions but had no impact on n-3 TG emulsions. Pre-injection of heparin increased and Triton WR 1339 and lactoferrin decreased blood clearance of n-6 TG emulsions with little or no effect on n-3 TG emulsions. Liver uptake of n-6 TG emulsions increased after heparin injection and decreased after Triton WR 1339 injection, but uptake of n-3 TG emulsions was not changed. These data show that the catabolism of n-3 TG emulsions and the catabolism of n-6 TG emulsions occur via very different mechanisms. Removal of chylomicron-sized n-6 TG emulsions is modulated by lipoprotein lipase (LPL), apoE, LDL-R, and lactoferrin-sensitive pathways. In contrast, clearance of chylomicron-sized n-3 TG emulsions relies on LPL to a very minor extent and is independent of apoE, LDL-R, and lactoferrin-sensitive pathways.

Animals↗
PubMed2002

Pregnancy-associated obesity in black women in New York City.

OBJECTIVE: To determine weight gain during pregnancy and weight changes postpartum in first-time mothers delivering at or near term. METHODS: At about 2 weeks after delivery, 47 adult, Black and Hispanic women provided information on their prepregnancy weight and height and maximum pregnancy weight. Women reinterviewed at 2 and 6 months after delivery reported their most recent weight measurement and the date of that measurement. This information was used to compute each woman's prepregnancy body mass index, pregnancy weight gain, and weight loss postpartum. Information on infant feeding was also collected at each postpartum visit. RESULTS: About 2/3 of the women and 100% of the overweight and obese women gained excessive weight during pregnancy. Weight gain was most marked in women who started pregnancy overweight or obese. At 2 months postpartum, women were on average almost 18 lb above their prepregnancy weight. No additional maternal weight was lost by 6 months postpartum. Most infants were started on formula by 2 weeks of age. At 2 months of age, 85% were fed formula only and 91% of the infants were on WIC. CONCLUSIONS: Our results demonstrate a need for interventions to help women avoid obesity by regulating their pregnancy weight gain, losing weight for a longer period postpartum, and initiating and maintaining exclusive breast-feeding.

Adolescent↗
PubMed2002

Intestinal protein loss in acute and persistent diarrhea of early childhood.

GOALS: To determine fecal protein loss in children with acute and persistent diarrhea. BACKGROUND: In children with diarrhea, ongoing losses of endogenous proteins have been suggested as contributing to impairment of nutritional and immunologic status. However, there is a paucity of information and inconclusive data in the literature. STUDY: Fecal protein loss was assessed prospectively in children (<3 years of age) with acute diarrhea (<7 days' duration) or persistent diarrhea (>14 days) and in controls using alpha-1-antitrypsin determination; fecal protein loss then was correlated with age, duration of diarrhea, nutritional status, plasma proteins, and stool pathogens. RESULTS: Children with acute diarrhea (n = 43) and those with persistent diarrhea (n = 41) had significantly higher fecal alpha-1-antitrypsin levels compared with controls (n = 14) (2.26 +/- 1.71 and 2.25 +/- 1.51, respectively, vs. 1.02 +/- 0.73 mg/g stools; p = 0.002). However, there was no significant decrease of plasma albumin, globulin, or immunoglobulins. Fecal protein loss did not differ significantly among stool pathogens (bacterial, viral, and parasitic) and demonstrated no significant correlation with age, duration of diarrhea, or nutritional status (mild malnutrition). CONCLUSIONS: Enhanced fecal protein loss was observed in more than 50% of children with acute and persistent diarrhea caused by various pathogens. This did not correlate with age, duration of diarrhea, or nutritional status and did not result in significant decrease of plasma proteins or immunoglobulins. This protein-losing enteropathy does not appear to have a causal role in perpetuation of diarrheal episodes in children with mild malnutrition.

Acute Disease↗
PubMed2002

Long-chain polyunsaturated fatty acid accretion in brain.

Brain is highly enriched in long-chain polyunsaturated fatty acids (PUFAs), particularly arachidonic acid and docosahexaenoic acid, which play important roles in brain structural and biologic functions. Plasma transport, in the form of free fatty acids or esterified FAs in lysophosphatidylcholine and lipoproteins, and de-novo synthesis contribute to brain accretion of long-chain PUFAs. Transport of long-chain PUFAs from plasma may play important roles because of the limited ability of brain to synthesize long-chain PUFAs, in the face of high demand for them. Although several proteins involved in facilitated fatty acid transport (e.g. fatty acid transport protein, fatty acid binding protein and very-long-chain acyl-coenzyme A synthetase) have been found in brain, their roles in fatty acid accumulation in brain are poorly defined. The primary pathways that are involved in long-chain PUFA accumulation in brain may vary according to brain region and developmental stage.

Arachidonic Acid↗
PubMed2001

Unsaturated fatty acid-mediated decreases in sterol regulatory element-mediated gene transcription are linked to cellular sphingolipid metabolism.

A major physiological feedback mechanism of cholesterol in transcription of a number of lipid metabolism-related genes is mediated by sterol regulatory elements (SREs) and their binding proteins (SREBPs). Polyunsaturated free fatty acids alone, as well as synergistically with sterols, decrease SRE-mediated gene expression up to 80% in a dose-dependent manner by decreasing levels of the active transcription factor SREBP. We investigated potential mechanisms for this effect. We hypothesized that free fatty acids reduce SREBP-mediated gene transcription by increasing intracellular cholesterol content through the hydrolysis of cellular sphingomyelin, which has a high affinity for free cholesterol. We also questioned whether the lipid second messenger ceramide, a product of sphingomyelin hydrolysis, can decrease SRE-mediated gene transcription. First we investigated the effect of fatty acids on sphingomyelin hydrolysis. Incubation of [(3)H]choline-labeled cells with unsaturated (but not saturated) fatty acids induced hydrolysis of [(3)H]choline-labeled sphingomyelin. Also, incubation of cell extracts from fatty acid-treated cells with [(3)H]sphingomyelin increased generation of [(3)H]ceramide compared with control cells in vitro. We found that addition of ceramide analogs alone and additively with fatty acids decreased SRE expression and that ceramide analogs reduced levels of the transcriptionally active forms of SREBP-1 and SREBP-2. Increasing intracellular ceramide levels by exogenous sphingomyelinase or inhibition of ceramidase decreased SRE-mediated gene expression. None of the above conditions induced apoptosis. Incubation with U18666A, a compound that inhibits intracellular cholesterol movement, increased SRE-mediated gene transcription. C(2)-ceramide abrogated the effect of U18666A on SRE-mediated gene transcription, suggesting cholesterol-independent regulation of SREBP. We provide evidence that sphingomyelin hydrolysis and intermediates of sphingomyelin metabolism (in addition to cholesterol and fatty acids) contribute to regulation of SRE-mediated gene transcription.

Animals↗
PubMedDate not supplied

Effects of particle size on blood clearance and tissue uptake of lipid emulsions with different triglyceride compositions.

BACKGROUND: Particle size of IV lipid emulsions affects the catabolism of long-chain triglyceride (LCT) emulsions, but little is known about its effect on the catabolism of medium-chain triglyceride (MCT)- and fish oil (FO)-containing emulsions. METHODS: Large (VLDL size), intermediate, and small (IDL size) emulsions with different triglyceride (TG) compositions were labeled with [3H]cholesteryl oleoyl ether: LCT (triolein 100%), MCT:LCT (trioctanoin:triolein 50%:50%), MCT:LCT:FO (trioctanoin:triolein:triDHA 50%:40%:10%), and FO (triDHA 100%). Emulsions (0.4 mg TG/mouse) were injected into C57BL/6J mice, and blood clearance and tissue uptake of emulsion particles were determined. RESULTS: Large emulsion particles had 2- to 3-fold faster fractional catabolic rates (FCR) compared with small particles with the same TG content. There was 1.5- to 2.0-fold higher FCR of large FO-containing emulsions (FO and MCT:LCT:FO) compared with large LCT and MCT:LCT emulsions, whereas effects of FO on FCR in small emulsions were not observed. Large FO-containing emulsions were taken up more by adipose tissue compared with small particles with concomitant decreases in hepatic uptake. Preinjection of heparin reduced heart and adipose uptakes of FO and MCT:LCT:FO emulsions with increased uptake by liver, suggesting a role of lipoprotein lipase in catabolism of FO-containing emulsions. CONCLUSIONS: In a mouse model, FO addition to large emulsions increased blood clearance and changed organ delivery. In contrast, there was no or little effect when particle size became smaller. We hypothesize that in humans, FO addition to lipid emulsions can help target emulsion delivery to certain extrahepatic tissues, a factor that may be of use for delivering specific fatty acids, or even drugs, to specific organs.

Analysis of Variance↗