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A R Tall

Publications and source records attributed to A R Tall.

At least 73 records · Page 4Linked to original sources
PubMed1997

Cholesteryl ester transfer protein activity enhances plasma cholesteryl ester formation. Studies in CETP transgenic mice and human genetic CETP deficiency.

The plasma cholesteryl ester transfer protein (CETP) promotes the removal of HDL cholesteryl esters and is thought to stimulate reverse cholesterol transport (RCT). However, mechanisms by which CETP may stimulate RCT are poorly understood. Thus, we examined the relationship between plasma CETP expression and plasma cholesteryl ester formation in CETP transgenic (Tg) mice, hamsters, and human subjects with genetic CETP deficiency. Incubation of CETP Tg mouse plasma showed a 20% to 40% increase in plasma cholesterol esterification rate (CER, P < .05) compared with control mice. Injection of a neutralizing CETP monoclonal antibody (MAb) (TP2) into natural flanking region CETP Tg mice resulted in an increase in plasma free cholesterol (FC) concentration, FC/CE ratio, FC/phosphatidylcholine ratio, and hepatic CETP mRNA. In hamsters, CETP inhibition also resulted in an increase in plasma FC/phosphatidylcholine ratio and increased CETP mRNA in adipose tissue. In humans with two common CETP gene mutations (an intron 14 splicing defect and a D442G missense mutation), mean plasma CERs were 39 and 60, respectively, compared with 89 nmol x mL-1 x h-1 in normal subjects. By contrast, lecithin:cholesterol acyltransferase (LCAT) mass was normal in CETP-deficient subjects. MAb neutralization of CETP activity in incubated human plasma did not alter the LCAT reaction, even after supplementation with discoidal HDL and VLDL. Thus, genetic alterations in CETP levels lead to secondary changes in the plasma LCAT reaction, possibly because of remodeling of HDL by CETP acting in concert with other factors in vivo. In human genetic CETP deficiency, a moderate impairment in the plasma LCAT reaction may contribute to a defect in RCT, providing a potential mechanism to explain the recently observed excess of coronary heart disease in these subjects.

Animals↗
PubMed1996

Human cholesteryl ester transfer protein gene proximal promoter contains dietary cholesterol positive responsive elements and mediates expression in small intestine and periphery while predominant liver and spleen expression is controlled by 5'-distal sequences. Cis-acting sequences mapped in transgenic mice.

The plasma cholesteryl ester transfer protein (CETP) facilitates the transfer of high density lipoprotein cholesteryl esters to other lipoproteins and appears to be a key regulated component of reverse cholesterol transport. Earlier studies showed that a CETP transgene containing natural flanking sequences (-3.4 kilobase pairs (kbp) upstream, +2.2 kbp downstream) was expressed in an authentic tissue distribution and induced in liver and other tissues in response to dietary or endogenous hypercholesterolemia. In order to localize the DNA elements responsible for these effects, we prepared transgenic mice expressing six new DNA constructs containing different amounts of natural flanking sequence of the CETP gene. Tissue-specific expression and dietary cholesterol response of CETP mRNA were determined. The native pattern of predominant expression in liver and spleen with cholesterol induction was shown by a -3.4 (5'), +0.2 (3') kbp transgene, indicating no major contribution of distal 3'-sequences. Serial 5'-deletions showed that a -570 base pairs (bp) transgene gave predominant expression in small intestine with cholesterol induction of CETP mRNA in that organ, and a -370 bp transgene gave highest expression in adrenal gland with partial dietary cholesterol induction of CETP mRNA and plasma activity. Further deletion to -138 bp 5'-flanking sequence resulted in a transgene that was not expressed in vivo. Both the -3.4 kbp and -138 bp transgenes were expressed when transfected into a cultured murine hepatocyte cell line, but only the former was induced by treating the cells with LDL. When linked to a human apoA-I transgene, the -570 to -138 segment of the CETP gene promoter gave rise to a relative positive response of hepatic apoA-I mRNA to the high cholesterol diet in two out of three transgenic lines. Thus, 5'-elements between -3,400 and -570 bp in the CETP promoter endow predominant expression in liver and spleen. Elements between -570 and -370 are required for expression in small intestine and some other tissues, and elements between -370 and -138 contribute to adrenal expression. The minimal CETP promoter element associated with a positive sterol response in vivo was found in the proximal CETP gene promoter between -370 and -138 bp. This region contains a tandem repeat of a sequence known to mediate sterol down-regulation of the HMG-CoA reductase gene, suggesting either the presence of separate positive and negative sterol response elements in this region or the use of a common DNA element for both positive and negative sterol responses.

Animals↗
PubMed1996

Increased prebeta-high density lipoprotein, apolipoprotein AI, and phospholipid in mice expressing the human phospholipid transfer protein and human apolipoprotein AI transgenes.

Human plasma phospholipid transfer protein (PLTP) circulates bound to high density lipoprotein (HDL) and mediates both net transfer and exchange of phospholipids between different lipoproteins. However, its overall function in lipoprotein metabolism is unknown. To assess the effects of increased plasma levels of PLTP, human PLTP transgenic mice were established using the human PLTP gene driven by its natural promoter. One line of PLTP transgenic mice with moderate expression of PLTP mRNA and protein was obtained. The order of human PLTP mRNA expression in tissues was: liver, kidney, brain, small intestine > lung > spleen > heart, adipose tissue. Western blotting using a human PLTP monoclonal antibody revealed authentic human PLTP (Mr 80 kD) in plasma. Plasma PLTP activity was increased by 29% in PLTP transgenic mice. However, plasma lipoprotein analysis, comparing PLTP transgenic mice to control littermates, revealed no significant changes in the plasma lipoprotein lipids or apolipoproteins. Since previous studies have shown that human cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase only function optimally in human apoAI transgenic mice, the human PLTP transgenic mice were cross-bred with human apoAI transgenic mice. In the human apoAI transgenic background, PLTP expression resulted in increased PLTP activity (47%), HDL phospholipid (26%), cholesteryl ester (24%), free cholesterol (37%), and apoAI (22%). There was a major increase of apoAI in prebeta-HDL (56%) and a small increase in alpha-HDL (14%). The size distribution of HDL particles within alpha- and prebeta-migrating species was not changed. The results suggest that PLTP increases the influx of phospholipid and secondarily cholesterol into HDL, leading to an increase in potentially antiatherogenic prebeta-HDL particles.

Animals↗
PubMed1996

Scavenger receptor BI (SR-BI) is up-regulated in adrenal gland in apolipoprotein A-I and hepatic lipase knock-out mice as a response to depletion of cholesterol stores. In vivo evidence that SR-BI is a functional high density lipoprotein receptor under feedback control.

Scavenger receptor BI (SR-BI), a putative high density lipoprotein (HDL) receptor, mediates the selective uptake of HDL cholesteryl ester into cells and is highly expressed in adrenal gland (Acton, S., Rigotti, A., Landschulz, K.T., Xu, S., Hobbs, H.H., and Krieger, M. (1996) Science 271, 518-520). Apolipoprotein A-I knock-out (apoA-I0) mice have decreased HDL cholesterol, depleted adrenal cholesterol stores and impaired corticosteroid synthesis (Plump, A.S., Erickson, S.K., Weng, W., J. Clin. Invest. 97, 2660-2671). We now show up-regulation of adrenal SR-BI mRNA and protein in apoA-I0 mice, but not in apoA-II0, LDL receptor 0, apoE0, or cholesteryl ester transfer protein transgenic mice. Adrenal SR-BI mRNA and protein are also increased and cholesterol stores decreased in female mice with knockout of hepatic lipase, and enzyme previously shown to increase selective uptake in cell culture. SR-BI mRNA is increased in stressed wild type mice and in Y1 adrenal cells treated with adrenocorticotropic hormone; the latter effect is inhibited by HDL. These findings provide in vivo evidence showing SR-BI is a functional HDL receptor under feedback control. The action of hepatic lipase on apoA-I-containing lipoproteins may facilitate the SR-BI-mediated uptake of HDL lipid.

Adrenal Glands↗
PubMed1996

Increased coronary heart disease in Japanese-American men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels.

Plasma high density lipoprotein (HDL) levels are strongly genetically determined and show a general inverse relationship with coronary heart disease (CHD). The cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to other lipoproteins and is a key participant in the reverse transport of cholesterol from the periphery to the liver. A high prevalence of two different CETP gene mutations (D442G, 5.1%; intron 14G:A, 0.5%), was found in 3,469 men of Japanese ancestry in the Honolulu Heart Program and mutations were associated with decreased CETP (-35%) and increased HDL chol levels (+10% for D442G). However, the overall prevalence of definite CHD was 21% in men with mutations and 16% in men without mutations. The relative risk (RR) of CHD was 1.43 in men with mutations (P < .05); after adjustment for CHD risk factors, the RR was 1.55 (P = .02); after additional adjustment for HDL levels, the RR was 1.68 (P = .008). Similar RR values were obtained for the D442G mutation alone. Increased CHD in men with mutations was primarily observed for HDL chol 41-60 mg/dl; for HDL chol > 60 mg/dl men with and without mutations had low CHD prevalence. Thus, genetic CETP deficiency appears to be an independent risk factor for CHD, primarily due to increased CHD prevalence in men with the D442G mutation and HDL cholesterol between 41 and 60 mg/dl. The findings suggest that both HDL concentration and the dynamics of cholesterol transport through HDL (i.e., reverse cholesterol transport) determine the anti-atherogenicity of the HDL fraction.

Aged↗
PubMed1996

Alternative splicing of the human cholesteryl ester transfer protein gene in transgenic mice. Exon exclusion modulates gene expression in response to dietary or developmental change.

The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester from high density lipoprotein to other lipoproteins. The human DETP gene produces two forms of mRNA, with or without exon 9 (E9)-derived sequences. To study the function and regulation of alternative splicing the CETP gene, transgenic mice were prepared 1) with the metallothionein (mT) promoter driving an E9-deleted construct (mT.CETP(-E9) transgene), and 2) with the natural flanking regions (NFR) controlling expression of genomic sequences which permit alternative splicing of E9 (NFR.CETP(+/-E9) transgene). With zinc induction, the mT.CETP(-E9) transgene gave rise to abundant E9-deleted CETP mRNA in liver and small intestine, but only relatively small amounts of E9-deleted protein were found in plasma. The E9-deleted form of CETP was inactive in lipid transfer and produced no changes in plasma lipoprotein profile. The NFR.CETP(+/-E9) transgene gave rise to full-length (FL) and E9-deleted forms of CETP mRNA in liver and spleen. In response to hypercholesterolemia induced by diet and breeding into an apoE gene knock-out background, the FL CETP mRNA was induced more than the E9-deleted mRNA, resulting in a 2-fold increase in ratio of FL/E9-deleted mRNA. The expression of CETP mRNA was found to be developmentally regulated. In NFR.CETP(+/-E9) transgenic mice CETP mRNA levels were markedly increased in the liver and small intestine in the perinatal period and decreased in adult mice, whereas CETP mRNA in the spleen was low in perinatal mice and increased in adults. The developmental increase in CETP mRNA in the liver and spleen was preceded by an increased ratio of FL/E9-deleted forms. Thus, the E9-deleted mRNA appears to be poorly translated and/or secreted, and the cognate protein is inactive in lipid transfer and lipoprotein metabolism. CETP gene expression was found to be highly regulated in a tissue-specific fashion during development. Increased CETP gene expression during development or in response to hypercholesterolemia is associated with preferential accumulation of the full-length CETP mRNA.

Alternative Splicing↗
PubMed1996

Profound induction of hepatic cholesteryl ester transfer protein transgene expression in apolipoprotein E and low density lipoprotein receptor gene knockout mice. A novel mechanism signals changes in plasma cholesterol levels.

The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to other lipoproteins and is a key regulated component of reverse cholesterol transport. Dietary hypercholesterolemia results in increased hepatic CETP gene transcription and higher plasma CETP levels. To investigate the mechanisms by which the liver senses hypercholesterolemia, mice containing a natural flanking region CETP transgene (NFR-CETP transgene) were bred with apo E or LDL receptor gene knockout mice (E0 or LDLr0 mice). Compared to NFR-CETP transgenic (Tg) mice with intact apo E genes, in NFR-CETP Tg/E0 mice there was an eightfold induction of plasma CETP levels and a parallel increase in hepatic CETP mRNA levels. Other sterol-responsive genes (LDL receptor and hydroxymethyl glutaryl CoA reductase) also showed evidence of altered regulation with decreased abundance of their mRNAs in the E0 background. A similar induction of plasma CETP and hepatic CETP mRNA levels resulted from breeding the NFR-CETP transgene into the LDL receptor gene knockout background. When placed on a high cholesterol diet, there was a further increase in CETP levels in both E0 and LDLr0 backgrounds. In CETP Tg, CETP Tg/E0, and CETP Tg/LDLr0 mice on different diets, plasma CETP and CETP mRNA levels were highly correlated with plasma cholesterol levels. The results indicate that hepatic CETP gene expression is driven by a mechanism which senses changes in plasma cholesterol levels independent of apo E and LDL receptors. Hepatic sterol-sensitive genes have mechanisms to sense hypercholesterolemia that do not require classical receptor-mediated lipoprotein uptake.

Animals↗
PubMed1995

Point mutagenesis of positively charged amino acids of cholesteryl ester transfer protein: conserved residues within the lipid transfer/lipopolysaccharide binding protein gene family essential for function.

The cholesteryl ester transfer protein (CETP) binds to plasma lipoproteins and transfers neutral lipids between them. Previous studies showed that lipoprotein binding involves ionic interactions between CETP and lipoproteins, with increased binding of CETP to lipoproteins carrying increased negative charge. In order to understand the molecular determinants of lipoprotein binding in CETP, site-directed mutagenesis was carried out on positively charged amino acids within and outside regions of conserved sequence in the putative family of lipid transfer/lipopolysaccharide (LPS) binding proteins (LT/LBP). Within the conserved regions, two mutant proteins, K233A and R259D, were well secreted by the transfected cells but showed markedly reduced cholesteryl ester transfer activity. Separating the bound from free CETP by gel filtration after incubation with HDL, HDL binding by K233A was found to be impaired, suggesting that the binding deficiency of the mutant may be responsible for decreased transfer activity. Kinetic analysis showed a marked increase in the apparent Km but no change in Vmax, consistent with a lipoprotein binding defect. Thus, within CETP, K233 and R259 play an essential role in cholesteryl ester transfer activity probably by mediating binding of CETP to lipoproteins. Sequence alignment of CETP, phospholipid transfer protein, LPS binding protein, and bactericidal permeability-inducing protein showed that K223 and R259 were strictly conserved as positively charged amino acids, suggesting a common function within the LT/LBP gene family.

Acute-Phase Proteins↗
PubMed1995

Molecular determinants of plasma cholesteryl ester transfer protein binding to high density lipoproteins.

The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of neutral lipids between lipoproteins and is associated with high density lipoproteins (HDL). To understand the mechanism of interaction of CETP with HDL, we studied the binding of pure recombinant CETP to 1-palmitoyl-2-oleoylphosphatidylcholine (POPC)/apoA-I discoidal particles. Separating bound from free CETP using native gradient gel electrophoresis, complexes of CETP with 10-nm hydrodynamic diameter discoidal particles migrated with a diameter of 12-16 nm, compared with approximately 7.5 nm for CETP. At lower ratios of CETP to discs, CETP bound to discs without displacement of apoA-I. CETP alone was unable to generate discoidal complexes. Cross-linking and fluorescence resonance energy transfer experiments indicated that CETP bound to discs as monomers. Cross-linking of CETP to apoA-I in discs suggested proximity of apoA-I and CETP. By negative-stain electron microscopy, discoidal complexes containing CETP and CETP monoclonal antibody showed localization of antibody molecules to the disc edge, suggesting that CETP was bound to the disc edge. The binding of CETP to discs of different composition or size was studied. Discs (10-nm Stokes diameter) prepared with either apoA-I or apoA-II had a similar Kd (120 nM). Inclusion of 1 mol % cholesteryl oleate, 5 mol % cholesterol, or 6 mol % phosphatidylinositol increased the binding affinity of CETP 3-10 times (20-30 nM). In comparison, plasma HDL3 had a Kd of approximately 450 nM. For POPC/apoA-I discs, 10-nm discs bound CETP with much higher affinity than smaller 7.8-nm discs (Kd = 1-2 microM). 7.7-nm hydrodynamic diameter POPC/apoA-I spherical particles containing either triolein or cholesteryl oleate in their core bound CETP with higher affinity (Kd = 50-100 nM) than 7.8-nm POPC/apoA-I discs. Thus, CETP appears to bind to the perimeter of discoidal particles, possibly in a process in which flexible segments in apoA-I or apoA-II accommodate CETP at the disc edge. The binding of CETP to HDL is markedly influenced by overall particle size and shape and by lipid composition, and the increased binding affinity for cholesterol- and cholesteryl ester-containing discs suggests a higher affinity of CETP for nascent than mature HDL.

Animals↗
PubMed1995

Cholesteryl ester transfer proteins, reverse cholesterol transport, and atherosclerosis.

Plasma cholesteryl ester transfer protein plays a central role in lipoprotein metabolism by exchanging cholesteryl esters with triglycerides. Human genetic deficiency is associated with increased HDL-cholesterol levels, whereas cholesteryl ester transfer protein overexpression in transgenic mice results in decreased HDL-cholesterol. Thus, it has been proposed that cholesteryl ester transfer protein deficiency is an antiatherogenic state. However, recent observations in human cholesteryl ester transfer protein deficiency and cholesteryl ester transfer protein transgenic mice also suggest antiatherogenic effects of the expression of this protein, probably reflecting its role in reverse cholesterol transport.

Animals↗
PubMed1995

Plasma cholesteryl ester transfer protein and high-density lipoproteins: new insights from molecular genetic studies.

Recent studies in transgenic mice provide strong evidence for a direct anti-atherogenic role of high-density lipoproteins (HDL) and highlight the importance of multiple gene interactions in the regulation of HDL levels. Plasma lipid transfer processes mediated by cholesteryl ester transfer protein (CETP) have a major impact on HDL levels, as revealed in studies of human genetic CETP deficiency and CETP transgenic mice. Subsequent to the discovery of an intron 14 CETP gene splicing defect, several new CETP gene mutations have been discovered recently in Japanese and other populations. One of these is an exon 15 missense mutation, changing amino acid 442 of CETP from aspartate to glycine. Population studies in Japan indicate that CETP gene mutations are sufficiently common to have a significant influence on HDL levels in the general population. Studies in transgenic mice show that CETP expression results in decreased levels of HDL cholesterol, but that the effects of CETP on HDL apolipoprotein A-I (apoA-I) content and size show important modulation by co-expression with transgenes encoding human apoA-I, apoC-III and apoA-II. In addition to the apparent antiatherogenic phenotype of human genetic CETP deficiency, high level expression of CETP in transgenic mice leads to accelerated atherosclerosis, illustrating the pro-atherogenic potential of CETP expression.

Animals↗
PubMed1995

Relation between cholesterol ester transfer protein activities and lipoprotein cholesterol in patients with hypercholesterolemia and combined hyperlipidemia.

Cholesterol ester transfer protein (CETP) promotes the transfer of cholesterol esters among different lipoprotein classes-high-density lipoproteins (HDL), very-low-density lipoproteins, intermediate-density lipoproteins, and low-density lipoproteins (LDL). The current study was carried out to determine whether CETP activities are correlated with lipoprotein cholesterol levels in a large number of patients having elevated LDL cholesterol and normal triglycerides (hypercholesterolemia) and elevated LDL cholesterol and high triglycerides (combined hyperlipidemia). Compared with 50 normolipidemic male patients, 113 hypercholesterolemic patients had a 42% higher mean activity of CETP, and approximately 60% of these patients had CETP activities outside the normal range. A similar elevation of CETP was observed in 47 patients with combined hyperlipidemia. Furthermore, in those with combined hyperlipidemia, CETP activities were highly correlated with LDL cholesterol, non-HDL cholesterol, and non-HDL/HDL ratios. Similar high correlations were obtained by combining normotriglyceridemic patients with and without elevated LDL cholesterol. Since patients with elevated LDL cholesterol had a significantly lower mean level of HDL cholesterol, a high CETP activity also was related to a reduced HDL cholesterol level. Our results are consistent with this concept, although they do not constitute final proof that high CETP activities contribute to elevated cholesterol concentrations and reduced HDL cholesterol levels in patients with hypercholesterolemia and in those with combined hyperlipidemia.

Aged↗
PubMed1995

Increases in dietary cholesterol are associated with modest increases in both LDL and HDL cholesterol in healthy young women.

We studied the effects of dietary cholesterol intake on lipid and lipoprotein levels in healthy young women (n = 13) who were otherwise eating an American Heart Association (AHA) diet. The study used a randomized, three-way crossover design to determine the effects of 0, 1, or 3 eggs added per day (dietary cholesterol range, 108 to 667 mg/d). Each of the three diets was eaten for 8 weeks, with a washout period between diets. Three fasting blood samples were obtained during the last 3 weeks of each diet period to observe changes in fasting plasma lipid levels associated with the menstrual cycle. We also obtained blood just before and 4 and 8 hours after the subjects ingested a standard high-fat formula. During the menstrual cycle, total cholesterol and LDL cholesterol levels fell by 0.051 mmol/L (1.99 mg/dL) and 0.064 mmol/L (2.48 mg/dL) per week, respectively. HDL cholesterol concentrations increased by 0.060 mmol/L (2.3 mg/dL) per week during the first half of the cycle and then fell by 0.050 mmol/L (1.94 mg/dL) per week during the second half. Therefore, all statistical analyses were performed on values adjusted to midcycle. Total fasting cholesterol concentrations increased by 0.073 mmol/L (2.81 mg/dL) per 100 mg dietary cholesterol added to the diet per day (P = .001). LDL cholesterol increased by 0.054 mmol/L (2.08 mg/dL) per 100 mg/d dietary cholesterol (P = .003); this accounted for about 75% of the rise in total cholesterol. HDL cholesterol concentrations increased by 0.015 mmol/L (0.57 mg/dL) per 100 mg/d dietary cholesterol (P < .04). There was a wide range of responses among the women. Plasma apoB levels increased significantly, 0.93 mg/dL per 100 mg/d dietary cholesterol (P = .025), whereas apoA-I levels tended to rise (1.35 mg/dL per 100 mg/d, P = .056). Increases in dietary cholesterol did not produce any observable effects on fasting plasma cholesteryl ester transfer protein levels and had no effect on the response to a standard high-fat formula. Although menstrual-cycle changes in plasma total, LDL, and HDL cholesterol levels were observed, the effects of the diets were similar in the follicular and luteal phases of the menstrual cycle. Additionally, despite changes associated with the menstrual cycle, within-subject variation in plasma total cholesterol was actually smaller in this study than in our study of young men.

Adult↗
PubMed1995

Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene.

The human cholesteryl ester transfer protein (CETP) facilitates the transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins. The activity of CETP results in a reduction in HDL cholesterol levels, but CETP may also promote reverse cholesterol transport. Thus, the net impact of CETP expression on atherogenesis is uncertain. The influence of hypertriglyceridemia and CETP on the development of atherosclerotic lesions in the proximal aorta was assessed by feeding transgenic mice a high cholesterol diet for 16 wk. 13 out of 14 (93%) hypertriglyceridemic human apo CIII (HuCIII) transgenic (Tg) mice developed atherosclerotic lesions, compared to 18 out of 29 (62%) controls. In HuCIII/CETPTg, human apo AI/CIIITg and HuAI/CIII/CETPTg mice, 7 of 13 (54%), 5 of 10 (50%), and 5 of 13 (38%), respectively, developed lesions in the proximal aorta (P < .05 compared to HuCIIITg). The average number of aortic lesions per mouse in HuCIIITg and controls was 3.4 +/- 0.8 and 2.7 +/- 0.6, respectively in HuCIII/CETPTg, HuAI/CIIIg, and HuAI/CIII/CETPTg mice the number of lesions was significantly lower than in HuCIIITg and control mice: 0.9 +/- 0.4, 1.5 +/- 0.5, and 0.9 +/- 0.4, respectively. There were parallel reductions in mean lesion area. In a separate study, we found an increased susceptibility to dietary atherosclerosis in nonhypertriglyceridemic CETP transgenic mice compared to controls. We conclude that CETP expression inhibits the development of early atherosclerotic lesions but only in hypertriglyceridemic mice.

Animals↗
PubMed1994

Interfacial properties of recombinant human cholesterol ester transfer protein.

We investigated the interfacial behavior of recombinant human cholesterol ester transfer protein (rCETP) using monolayer and surface balance techniques. rCETP bound to egg phosphatidylcholine monolayers spread at the air/water interface with a maximum surface pressure of 23 millinewtons (mN)/m at subphase concentrations between 3 and 5 x 10(-5) g/dl; the estimated dissociation constant was 7.5 x 10(-6) g/dl or 1 nM. The binding of rCETP to the lipid interface decreased linearly with increasing initial surface pressure; rCETP was excluded at pressures greater than 31 mN/m. rCETP catalyzed the desorption of [14C]cholesterol oleate from mixed lipid monolayers in a concentration dependent fashion. Similar studies with apolipoproteins A-I and A-IV established that cholesterol ester desorption was not caused by changes in surface pressure or cholesterol ester solubility. The desorption rate was proportional to subphase rCETP concentration, but at all concentrations surface radioactivity remained constant until surface pressure reached a plateau. The calculated binding stochiometry was one molecule of cholesterol ester desorbed for every 1000 molecules of rCETP in the subphase. We conclude that rCETP is surface active, binds to phospholipid monolayers with an affinity equivalent to that of the plasma apolipoproteins, and effects the desorption of cholesterol ester molecules from phospholipid monolayers by a carrier mechanism. Moreover, the relatively low equilibrium surface pressure of rCETP suggests that when bound to lipid the entire rCETP molecule may not penetrate the interface.

Adsorption↗
PubMed1994

A dose-response study of the effects of dietary cholesterol on fasting and postprandial lipid and lipoprotein metabolism in healthy young men.

Despite many previous studies, controversy remains concerning the effects of dietary cholesterol on plasma cholesterol concentrations. In addition, the focus of previous studies has been fasting lipid and lipoprotein concentrations; there are no published studies with postprandial measurements. We studied the effects of four levels of dietary cholesterol intake on fasting lipid, lipoprotein, and apoprotein levels, as well as postprandial lipid levels, in a group of young, healthy men who were otherwise eating a low-fat, American Heart Association step 1 diet. Twenty young, healthy men completed a randomized, four-way crossover design study to test the effects of an American Heart Association step 1 diet containing 0, 1, 2, or 4 eggs per day. Dietary cholesterol ranged from 128 to 858 mg cholesterol per day. Each diet was eaten for 8 weeks, with a break between diets. Three fasting blood samples were obtained at the end of each diet period. In addition, blood samples were obtained just before and 2, 4, and 6 hours after ingestion of a standard lunch containing the various amounts of egg cholesterol. We also obtained blood 4 and 8 hours after the subjects ingested a standard, high-fat formula. Fasting plasma total cholesterol concentrations increased by 1.47 mg/dL (0.038 mmol/L) for every 100 mg dietary cholesterol added to the diet (P < .001). Low-density lipoprotein (LDL) cholesterol increased in parallel. Responsiveness varied but appeared to be normally distributed. Fasting plasma apoprotein B concentrations increased approximately 10% between the 0- and 4-egg diets and were correlated with changes in total and LDL cholesterol concentrations. Although there was a trend toward a greater response in men with an apoprotein E4 allele, this was not statistically significant. Fasting plasma cholesteryl ester transfer protein levels were higher only on the 4-egg diet, and changes in cholesteryl ester transfer protein levels between the 0- and 4-egg diets correlated with changes in total and LDL cholesterol. There were no differences in the postlunch or post-fat-formula responses of plasma lipids across the diets. Incubation of the 4-hour postlunch serum with J774 macrophages did not affect cell cholesteryl ester content at any level of dietary cholesterol. Cellular free cholesterol levels were slightly higher on each of the egg-containing diets versus the 0-egg diet. In summary, increases in dietary cholesterol resulted in linear increases in fasting total and LDL cholesterol in young, healthy men.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1994

Gender effects on the distribution of the cholesteryl ester transfer protein in apolipoprotein A-I-defined lipoprotein subpopulations.

Two subpopulations of apolipoprotein A-I-containing lipoproteins, those containing only apoA-I (LpA-I) and those containing both apoA-I and apoA-II (LpA-I/A-II), were isolated by immunoaffinity chromatography of plasma from 44 subjects, comprising four groups (male or female, with or without hyperlipidemia). ApoA-I-defined particles (LpAs) were assessed for their content of cholesteryl ester transfer protein (CETP) and for their ability to act as substrates for CETP. Although plasma CETP concentration was similar in all groups, the plasma concentration of LpA-I-associated CETP was significantly higher in females than in males (1.56 +/- 0.11 versus 0.93 +/- 0.13 mg/l, P < 0.05). In females, the major fraction of CETP was found in LpA-I, whereas in normolipidemic males CETP was evenly distributed between LpA-I and LpA-I/A-II, and in hyperlipidemic males the majority of CETP was found in LpA-I/A-II. In all groups, the percentage of CETP in LpA-I was correlated with the concentration of apoA-I in LpA-I (r = 0.64, P < 0.001). Native gradient gel electrophoresis of isolated LpAs showed that CETP was broadly distributed within different sized particles. LpA-I and LpA-I/A-II showed similar efficiency of CETP-mediated cholesteryl ester exchange with LDL. In conclusion, even though LpA-I has a much higher apparent affinity for CETP than LpA-I/A-II, both LpAs can bind CETP and act as equivalent CETP substrates in vitro. Thus, in subjects with low levels of LpA-I (notably hyperlipidemic males), most of the plasma neutral lipid exchange will involve LpA-I/A-II.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗