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C Fievet

Publications and source records attributed to C Fievet.

At least 19 recordsLinked to original sources
PubMed2001

Peroxisome proliferator-activated receptor-alpha regulates lipid homeostasis, but is not associated with obesity: studies with congenic mouse lines.

Considerable controversy exists in determining the role of peroxisome proliferator-activated receptor-alpha (PPARalpha) in obesity. Two purebred congenic strains of PPARalpha-null mice were developed to study the role of this receptor in modulating lipid transport and storage. Weight gain and average body weight in wild-type and PPARalpha-null mice on either an Sv/129 or a C57BL/6N background were not markedly different between genotypes from 3 to 9 months of age. However, gonadal adipose stores were significantly greater in both strains of male and female PPARalpha-null mice. Hepatic accumulation of lipids was greater in both strains and sexes of PPARalpha-null mice compared with wild-type controls. Administration of the peroxisome proliferator WY-14643 caused hepatomegaly, alterations in mRNAs encoding proteins that regulate lipid metabolism, and reduced serum triglycerides in a PPARalpha-dependent mechanism. Constitutive differences in serum cholesterol and triglycerides in PPARalpha-null mice were found between genetic backgrounds. Results from this work establish that PPARalpha is a critical modulator of lipid homeostasis in two congenic mouse lines. This study demonstrates that disruption of the murine gene encoding PPARalpha results in significant alterations in constitutive serum, hepatic, and adipose tissue lipid metabolism. However, an overt, obese phenotype in either of the two congenic strains was not observed. In contrast to earlier published work, this study establishes that PPARalpha is not associated with obesity in mice.

Animals↗
PubMed2001

Human ABCA1 BAC transgenic mice show increased high density lipoprotein cholesterol and ApoAI-dependent efflux stimulated by an internal promoter containing liver X receptor response elements in intron 1.

By using BAC transgenic mice, we have shown that increased human ABCA1 protein expression results in a significant increase in cholesterol efflux in different tissues and marked elevation in high density lipoprotein (HDL)-cholesterol levels associated with increases in apoAI and apoAII. Three novel ABCA1 transcripts containing three different transcription initiation sites that utilize sequences in intron 1 have been identified. In BAC transgenic mice there is an increased expression of ABCA1 protein, but the distribution of the ABCA1 product in different cells remains similar to wild type mice. An internal promoter in human intron 1 containing liver X response elements is functional in vivo and directly contributes to regulation of the human ABCA1 gene in multiple tissues and to raised HDL cholesterol, apoAI, and apoAII levels. A highly significant relationship between raised protein levels, increased efflux, and level of HDL elevation is evident. These data provide proof of the principle that increased human ABCA1 efflux activity is associated with an increase in HDL levels in vivo.

ATP Binding Cassette Transporter 1↗
PubMed2001

Induction of the phospholipid transfer protein gene accounts for the high density lipoprotein enlargement in mice treated with fenofibrate.

Fibrate treatment in mice is known to modulate high density lipoprotein (HDL) metabolism by regulating apolipoprotein (apo)AI and apoAII gene expression. In addition to alterations in plasma HDL levels, fibrates induce the emergence of large, cholesteryl ester-rich HDL in treated transgenic mice expressing human apoAI (HuAITg). The mechanisms of these changes may not be restricted to the modulation of apolipoprotein gene expression, and the aim of the present study was to determine whether the expression of factors known to affect HDL metabolism (i.e. phospholipid transfer protein (PLTP), lecithin:cholesterol acyltransferase, and hepatic lipase) are modified in fenofibrate-treated mice. Significant rises in plasma PLTP activity were observed after 2 weeks of fenofibrate treatment in both wild-type and HuAITg mice. Simultaneously, hepatic PLTP mRNA levels increased in a dose-dependent fashion. In contrast to PLTP, lecithin:cholesterol acyltransferase mRNA levels in HuAITg mice were not significantly modified by fenofibrate despite a significant decrease in plasma cholesterol esterification activity. Fenofibrate did not induce any change in hepatic lipase activity. Fenofibrate significantly increased HDL size, an effect that was more pronounced in HuAITg mice than in wild-type mice. This effect in wild-type mice was completely abolished in PLTP-deficient mice. Finally, fenofibrate treatment did not influence PLTP activity or hepatic mRNA in peroxisome proliferator-activated receptor-alpha-deficient mice. It is concluded that 1) fenofibrate treatment increases plasma phospholipid transfer activity as the result of up-regulation of PLTP gene expression through a peroxisome proliferator-activated receptor-alpha-dependent mechanism, and 2) increased plasma PLTP levels account for the marked enlargement of HDL in fenofibrate-treated mice.

Animals↗
PubMed2001

Metabolic effects of rexinoids: tissue-specific regulation of lipoprotein lipase activity.

Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid increase in serum triglyceride levels. LG268 has no effect on hepatic triglyceride production but suppresses post-heparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished peripheral processing of plasma very low density lipoproteins particles. Treatment of diabetic rats with rexinoids suppresses skeletal and cardiac muscle but not adipose tissue LPL activity. This effect is independent of changes in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surface (i.e., heparin-releasable) LPL activity without altering LPL mRNA. This effect is very rapid (t(1/2) = 2 h) and is blocked by the transcriptional inhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest that skeletal muscle may be an important target of rexinoid action. In addition, these data underscore that the metabolic consequences of RXR activation are distinct from either retinoic acid receptor or peroxisome proliferator-activated receptor activation.

Animals↗
PubMed2001

Increased levels of high-density lipoprotein cholesterol are ineffective in inhibiting the development of immune responses to oxidized low-density lipoprotein and atherosclerosis in transgenic rabbits expressing human apolipoprotein (apo) A-I with severe hypercholesterolaemia.

High levels of high-density lipoprotein (HDL) cholesterol have been reported to protect against the development of atherosclerosis in humans by increasing reverse cholesterol transport and inhibiting the oxidation of low-density lipoprotein (LDL) due to the paraoxonase content of HDL. The purpose of the present study was to assess if there are any relationships between in vivo increases in serum levels of immunological LDL oxidation markers [autoantibodies against oxidized LDL, autoantibodies against malondialdehyde-modified LDL, LDL immune complexes and anti-cardiolipin autoantibodies], paraoxonase activity and the development of atherosclerosis in control rabbits and in transgenic rabbits expressing human apolipoprotein (apo) A-I. A total of 13 apo A-I transgenic rabbits and 18 non-transgenic littermates were fed on a cholesterol-rich diet (0.4%, w/w) for 14 weeks, and were monitored at weeks 0, 2, 6, 10 and 14. Aortic atherosclerotic lesions were measured at the end of this period. Human apo A-I transgenic rabbits with high HDL cholesterol levels were not protected against the development of atherosclerosis when they were fed on a cholesterol-rich diet which induced dramatic hypercholesterolaemia. Immunological markers of LDL oxidation increased and serum paraoxonase activity decreased similarly in control and transgenic rabbits. In conclusion, the present study demonstrates that high HDL cholesterol levels are ineffective in inhibiting increases in immunological markers of LDL oxidation and the development of atherosclerosis in a mammal with severe hypercholesterolaemia.

Animals↗
PubMed2000

Loss of atheroprotective effect of estradiol in immunodeficient mice.

Estradiol significantly decreases fatty streak formation in the aortic root of chow-fed apolipoprotein E-deficient mice. In contrast, immunodeficient mice with homozygous disruption at the recombinase activating gene 2 loci present fatty streak development that is insensitive to estradiol. Lymphocytes thus appear to be required for development of the atheroprotective effect of estradiol in this mouse model.

Animals↗
PubMed2000

Measurement of rabbit apolipoprotein B by use of electroimmunodiffusion and immunonephelometric assays.

BACKGROUND AND PURPOSE: Because of their similarity to humans, rabbits are a good animal model for the study of atherosclerosis associated with high serum low-density lipoprotein (LDL) values. Two assays were developed to measure apolipoprotein B (apoB), the major structural and functional apolipoprotein of LDL in rabbits and to distinguish endogenous LDL in transgenic rabbits from that of human apoB. METHODS: Two procedures, an electroimmunoassay (EIA) and an immunonephelometric assay (INA), along with a goat-origin rabbit antiserum were developed to measure serum apoB concentration in rabbits. RESULTS: Use of either assay resulted in ability to measure rabbit species-specific apoB concentration. CONCLUSION: These assays should have broad applications: to screen compounds or diets that might lower serum apoB concentrations; to specifically measure human apoB concentration in transgenic rabbits; to measure serum apoB concentration in rabbits overexpressing other human proteins.

Animals↗
PubMed1999

Protective role of interleukin-10 in atherosclerosis.

The potential role of anti-inflammatory cytokines in the modulation of the atherosclerotic process remains unknown. Interleukin (IL)-10 has potent deactivating properties in macrophages and T cells and modulates many cellular processes that may interfere with the development and stability of the atherosclerotic plaque. IL-10 is expressed in human atherosclerosis and is associated with decreased signs of inflammation. In the present study, we show that IL-10-deficient C57BL/6J mice fed an atherogenic diet and raised under specific pathogen-free conditions exhibit a significant 3-fold increase in lipid accumulation compared with wild-type mice. Interestingly, the susceptibility of IL-10-deficient mice to atherosclerosis was exceedingly high (30-fold increase) when the mice were housed under conventional conditions. Atherosclerotic lesions of IL-10-deficient mice showed increased T-cell infiltration, abundant interferon-gamma expression, and decreased collagen content. In vivo, transfer of murine IL-10 achieved 60% reduction in lesion size. These results underscore the critical roles of IL-10 in both atherosclerotic lesion formation and stability. Moreover, IL-10 appears to be crucial as a protective factor against the effect of environmental pathogens on atherosclerosis.

Animals↗
PubMed1998

Branched synthetic peptide constructs mimic cellular binding and efflux of apolipoprotein AI in reconstituted high density lipoproteins.

This study investigates the suitability of the trimeric apolipoprotein (apo)AI(145-183) peptide that we recently described, to serve as a model to probe the relationship between apoAI structure and function. Three copies of the apoAI(145-183) unit, composed each of two amphipathic alpha-helical segments, were branched onto a covalent core matrix and the construct was recombined with phospholipids. A similar construct was made with the apoAI(102-140) peptide and used as a comparison with dimyristoylglycerophosphocholine (DMPC)-apoAI complexes. The DMPC-trimeric-apoAI(145-183) complexes had similar immunological reactivity with monoclonal antibodies directed against the 149-186 apoAI sequence (A44), suggesting that the A44 epitope is exposed similarly in both the synthetic peptide and the native apoAI complexes. The complexes generated with the trimeric-apoAI(145-183) bind specifically to HeLa cells with comparable affinity to the DMPC apoAI complexes; they are a good competitor for binding of apoAI to both HeLa cells and Fu5AH rat hepatoma cells; finally, these complexes promote cholesterol efflux from Fu5AH cells with an efficiency comparable with the apo AI/lipid complexes. To study LCAT activation by the trimeric apo AI(145-183) construct, complexes were prepared with dipalmitoylphosphatidylcholine (DPPC), cholesterol (C) and either the trimeric construct or apoAI. LCAT activation by the trimeric construct was much lower than by apo AI, possibly because the conformation of the trimeric 145-183 peptide in DPPC/C/peptide complexes does not mimic that of apoAI in the corresponding complexes. In comparison, the complexes generated with the multimeric apoAI(102-140) construct had a poor capacity to mimic the physico-chemical and biological properties of apoAI. The apoAI(102-140) construct had low affinity for lipid compared with the (145-183) construct. After association with lipids, it was a poor competitor of DMPC-apoAI complexes for cellular binding and had only limited capacity to promote cholesterol efflux. These results suggest trimeric constructs can serve as an appropriate models for apoAI, enabling further investigations and new experimental approaches to determine the structure-function relationship of apoAI.

Animals↗
PubMed1997

Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor alpha-deficient mice.

The peroxisome proliferator-activated receptor-alpha (PPARalpha) controls gene expression in response to a diverse class of compounds collectively referred to as peroxisome proliferators. Whereas most known peroxisome proliferators are of exogenous origin and include hypolipidemic drugs and other industrial chemicals, several endogenous PPARalpha activators have been identified such as fatty acids and steroids. The latter finding and the fact that PPARalpha modulates target genes encoding enzymes involved in lipid metabolism suggest a role for PPARalpha in lipid metabolism. This was investigated in the PPARalpha-deficient mouse model. Basal levels of total serum cholesterol, high density lipoprotein cholesterol, hepatic apolipoprotein A-I mRNA, and serum apolipoprotein A-I in PPARalpha-deficient mice are significantly higher compared with wild-type controls. Treatment with the fibrate Wy 14,643 decreased apoA-I serum levels and hepatic mRNA levels in wild-type mice, whereas no effect was detected in the PPARalpha-deficient mice. Administration of the fibrate Wy 14,643 to wild-type mice results in marked depression of hepatic apolipoprotein C-III mRNA and serum triglycerides compared with untreated controls. In contrast, PPARalpha-deficient mice were unaffected by Wy 14,643 treatment. These studies demonstrate that PPARalpha modulates basal levels of serum cholesterol, in particular high density lipoprotein cholesterol, and establish that fibrate-induced modulation in hepatic apolipoprotein A-I, C-III mRNA, and serum triglycerides observed in wild-type mice is mediated by PPARalpha.

Animals↗
PubMed1997

Cholesterol efflux, lecithin-cholesterol acyltransferase activity, and pre-beta particle formation by serum from human apolipoprotein A-I and apolipoprotein A-I/apolipoprotein A-II transgenic mice consistent with the latter being less effective for reverse cholesterol transport.

Studies assessing fatty streak formation in mice have revealed that human apolipoprotein A-I (apoAI) transgenic mice (TgAI) have 15-fold less atherosclerosis susceptibility than combined human apolipoprotein A-I/human apolipoprotein A-II (apoAI:AII) transgenics (TgAI:AII) and 40-fold less than nontransgenic control mice. In order to examine the biochemical mechanisms underlying those in vivo observations, we have compared in vitro properties of serum from the different groups of animals for participation in cholesterol efflux, LCAT activation, and pre-beta particle formation. Analysis of cholesterol efflux from both Fu5AH hepatoma and Ob1771 adipose cells revealed serum from the TgAI to be the most efficient in promoting efflux. The two-dimensional electrophoresis of mouse serum shows that control mice have exclusively apoAI in alpha particles. TgAI and TgAI:AII mice have 30 and 38% of total apoAI in particles with pre-beta electrophoretic mobility, respectively. The distribution of cell-derived cholesterol between these apoAI-containing lipoprotein subspecies after 1 and 60 min of incubation with Fu5AH hepatoma cells was examined. This revealed after a 1 min incubation 66 +/- 8 and 83 +/- 9% of the counts in particles with pre-beta mobility for TgAI and TgAI:AII mice, respectively; while after 60 min of incubation, only 6 +/- 2% of counts remained in pre-beta particles from the TgAI and 30 +/- 3% for the TgAI:AII. This suggests faster movement of cholesterol from pre-beta to alpha particles in plasma from the TgAI. Consistent with this is the observation that LCAT activity with both exogenous and endogenous substrate increased in the TgAI versus the TgAI:AII mice. The previously observed decrease in fatty streak formation in the TgAI versus the TgAI:AII and control mice is consistent with the in vitro studies presented here and suggests that HDL containing human apoAI is a more effective participant in the postulated early steps in reverse cholesterol transport than HDL containing both human apoAI and human apoAII, and/or murine HDL.

Animals↗
PubMed1997

Distribution of apolipoprotein E between apo B- and non apo B-containing lipoproteins according to apo E phenotype.

Apolipoprotein E (apo E) is a component of all the classes of lipoproteins and can be distributed among apo B- (LpB) and non apo B-containing lipoproteins (Lp-non-B). Using a new electroimmunoassay kit, plasma apo E, apo E in Lp-non-B (apo E-Lp-non-B) and apo E in LpB (apo E-LpB) levels were measured in healthy control subjects (n=481) from 3 centers participating in the ECTIM study (Etude Cas-Témoins sur l'Infarctus du Myocarde), a population-based study on myocardial infarction. The distribution of apo E among lipoproteins was analyzed according to the apo E phenotype after adjustment for center, body mass index, tobacco use, alcohol consumption and triglycerides. Apo E was higher (average excess: + 0.32; P < 0.0001) and lower (average excess: -0.12; P < 0.0001) in subjects carrying the allele epsilon2 and the allele epsilon4 respectively, than in apo E3/3 subjects. These differences are the consequence of variations in apo E-Lp-non-B which clearly differed between the groups classified according to their apo E phenotype (P < 0.0001). The average excess of apo E Lp non-B compared to apo E3/3 subjects was + 0.43 (P < 0.0001) and -0.22 (P < 0.0001) for the epsilon2 and epsilon4 alleles respectively. Apo E-LpB was lower in subjects carrying the epsilon2 allele (P < 0.02) while the presence of the epsilon4 allele did not modify this parameter. The proportion of apo E within HDL was clearly higher and lower in subjects carrying apo E2 and apo E4 respectively than in apo E3/3 subjects. Although triglyceride levels were dependent on the apo E phenotype, the adjustment of the proportion of apo E in HDL for triglycerides hardly modified the results. For the first time, these results, using direct measurements on a large number of subjects, confirm the greater preference of apo E4 over apo E2 for LpB and vice versa for Lp-non-B. They also show a greater affinity of apo E2 for HDL compared to apo E3. This high affinity of apo E2 for HDL could be due to the formation of the apo E-A-II complex. These results indicate that apo E phenotype modulates the distribution of apo E among lipoproteins and suggest differences in lipoprotein metabolism between apo E2, apo E3 and apo E4.

Adult↗
PubMed1997

Regulation of lipoprotein metabolism by thiazolidinediones occurs through a distinct but complementary mechanism relative to fibrates.

Thiazolidinediones are antidiabetic agents, which not only improve glucose metabolism but also reduce blood triglyceride concentrations. These compounds are synthetic ligands for PPAR gamma, a transcription factor belonging to the nuclear receptor subfamily of PPARs, which are important transcriptional regulators of lipid and lipoprotein metabolism. The goal of this study was to evaluate the influence of a potent thiazolidinedione, BRL49653, on serum lipoproteins and to determine whether its lipid-lowering effects are mediated by changes in the expression of key genes implicated in lipoprotein metabolism. Treatment of normal rats for 7 days with BRL49653 decreased serum triglycerides in a dose-dependent fashion without affecting serum total and HDL cholesterol and apolipoprotein (apo) A-I and apo A-II concentrations. The decrease in triglyceride concentrations after BRL49653 was mainly due to a reduction of the amount of VLDL particles of unchanged lipid and apo composition. BRL49653 treatment did not change triglyceride production in vivo as analyzed by injection of Triton WR-1339, indicating a primary action on triglyceride catabolism. Analysis of the influence of BRL49653 on the expression of LPL and apo C-III, two key players in triglyceride catabolism, showed a dose-dependent increase in mRNA levels and activity of LPL in epididymal adipose tissue, whereas liver apo C-III mRNA levels remained constant. Furthermore, addition of BRL49653 to primary cultures of differentiated adipocytes increased LPL mRNA levels, indicating a direct action of the drug on the adipocyte. Simultaneous administration of BRL49653 and fenofibrate, a hypolipidemic drug that acts primarily on liver through activation of PPAR alpha both decreased liver apo C-III and increased adipose tissue LPL mRNA levels, resulting in a more pronounced lowering of serum triglycerides than each drug alone. In conclusion, both fibrates and thiazolidinediones exert a hypotriglyceridemic effect. While fibrates act primarily on the liver by decreasing apo C-III production, BRL49653 acts primarily on adipose tissue by increasing lipolysis through the induction of LPL expression. Drugs combining both PPAR alpha and gamma activation potential should therefore display a more efficient hypotriglyceridemic activity than either compound alone and may provide a rationale for improved therapy for elevated triglycerides.

Adipose Tissue↗
PubMed1996

Inhibition of atherosclerosis development in cholesterol-fed human apolipoprotein A-I-transgenic rabbits.

BACKGROUND: Prospective epidemiological studies support the hypothesis that high levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I limit atherosclerosis development. However, more data from studies with animal models of atherosclerosis that resemble the human disease are required to demonstrate the effect of apo A-I in the inhibition of atherogenesis. The rabbit is a good animal model for human atherosclerosis. METHODS AND RESULTS: Human apo A-I-transgenic rabbits have been produced, and we have evaluated the effect of apo A-I on the development of atherosclerosis in transgenic rabbits fed a cholesterol-rich diet for 14 weeks. Plasma cholesterol levels of atherogenic apo B-containing lipoproteins were similar for transgenic and control rabbits (> 1000 mg/dL), while plasma levels of HDL cholesterol in the transgenic group were always about twice that of the control group (68 +/- 11 versus 37 +/- 3 mg/dL at 14 weeks; P < .001). At the end of the experiment, the amount of aortic surface area covered by lesions as well as the amount of lipid accumulation in the aorta were significantly less in transgenic rabbits compared with the control group (15 +/- 12% versus 30 +/- 8%, P < .0027 for the surface area of the thoracic aorta; 116 +/- 31 versus 247 +/- 39 mumol/g aorta, P < .0068 for cholesterol content in total aorta). CONCLUSIONS: Overexpression of human apo A-I in rabbits inhibits the development of atherosclerosis in this animal model that resembles, in many respects, human atherosclerosis.

Analysis of Variance↗
PubMed1996

Branched synthetic constructs that mimic the physico-chemical properties of apolipoprotein AI in reconstituted high-density lipoproteins.

Amphipathic helical repeats are considered as the structural units of numerous apolipoproteins and have been described as being responsible for the interaction of apolipoproteins with phospholipids in high-density lipoproteins (HDL). Furthermore, apolipoproteins, and especially apolipoprotein AI (apoAI), are involved in various biological functions of these circulating particles in plasma. Studies with synthetic peptides corresponding to domains of the apoAI sequence have however shown that short 39-residue fragments do not interact strongly enough with phospholipids to generate particles that correctly mimic the physico-chemical properties of HDL reconstituted with native apoAI [Vanloo, B., Demoor, L., Boutillon, C., Lins, L., Baert, J., Fruchart, J. C., Tartar, A. & Rosseneu, M. (1995) Association of synthetic peptide fragments of human apolipoprotein A-I with phospholipids, J. Lipid Res. 36, 1686-1696.]. Here we show that synthetic branched multimeric peptides, often used as carriers for the design of synthetic vaccines (multiple-antigen peptides), can be used to mimic the physiochemical properties of apoAI in HDL. This type of molecule is obtained by using a small core matrix of Lys residues bearing radially branched synthetic peptides as dendritic arms. We compared the lipid-binding capacities and the structural properties of a linear peptide corresponding to residues 145-183 of apoAI [apoAI-(145-183)-peptide] with those of two multimeric peptides consisting respectively of three [trimeric apoAI-(145-183)] and four copies [tetrameric apoAI-(145-183)] of the selected sequence, branched on a covalent core matrix. This paper provides evidence for the increased abilities of the multimeric peptides to associate with phospholipids compared with the short linear peptides. Moreover, the trimeric apoAI-(145-183) peptide was most efficient in mimicking the physico-chemical and structural properties of native apoAI in reconstituted HDL. As tools adequate to unravel the structure/function relationship of separate apolipoprotein domains are still missing, these multimeric peptides might constitute an alternative approach to linear peptides which are poor mimetics and to protein mutants which are difficult to produce and only provide information about the total sequence.

Amino Acid Sequence↗
PubMed1996

Intraperitoneal insulin infusion improves the depletion in choline-containing phospholipids of lipoprotein B particles in type I diabetic patients.

Insulin-dependent diabetes mellitus (IDDM) is characterized by altered composition of atherogenic lipoproteins, especially a depletion in choline-containing phospholipids (PL) of apolipoprotein (apo) B lipoproteins (LpB). To determine the effects of continuous intraperitoneal (IP) insulin infusion (CIPII) on this qualitative lipoprotein abnormality, we compared lipoprotein profiles of 14 IDDM patients treated by continuous subcutaneous insulin infusion (CSII) and at 2 and 4 months after treatment with CIPII using an implantable pump. IDDM patients were in fair metabolic control and were compared with 14 healthy control subjects matched for sex, age, body mass index, and plasma lipids. The following parameters were studies: hemoglobin A1c (HbA1c), monthly blood glucose, daily insulin dose (units per kilogram per day), total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol, apo A-I, and apo B. Choline-containing PL were assessed in plasma and in apo B- and no-apo B-containing lipoprotein particles (LpB and Lp no B). As compared with the control group, plasma PL and LpB-PL were significantly lower in IDDM patients treated by CSII (2.95 +/- 0.26 v 3.30 +/- 0.45 mmol/L,P<.05, and 1.09 +/- 0.45 v 1.68 +/- 0.33 mmol/L,P<.01, respectively). No significant differences were observed for Lp no B lipid determinations between both groups. After initiation of CIPII, IDDM patients did not experience any significant changes in mean values for body mass index, HbA1c, and monthly blood glucose throughout the study. Daily insulin doses were identical to those observed before IP therapy. Lipid parameters remained unchanged in IDDM patients (TC, TG, HDL and LDL cholesterol, apo A-I, and apo B). A moderate but progressive elevation of plasma PL was noted, and after 4 months of CIPII, PL and LpB-PL levels were no longer significantly different between IDDM patients and controls. The increase in plasma and LpB choline-containing PL observed after 2 and 4 months of CIPII is not linked to changes in blood glucose control, body weight or daily insulin requirements. These changes may be related to the route of insulin administration, which may be accompanied by a reduction of lipoprotein lipase (LPL) activity and consequently a reduction of phospholipase activity. These results suggest that IP insulin delivery may be a more physiological route that increases the choline-containing PL content of LpB particles.

Adult↗
PubMed1996

Transgenic rabbits expressing human apolipoprotein A-I in the liver.

Human apolipoprotein A-I (apo A-I) transgenic rabbits were created by use of an 11-kb genomic human apo A-I construct containing a liver-specific promoter. Five independent transgenic lines were obtained in which human apo A-I gene had integrated and was expressed. Plasma levels of human apo A-I ranged from 8 to 100 mg/dL for the founder and up to 175 mg/dL for the progeny. Rabbit apo A-I levels were substantially decreased in the transgenic rabbits. HDL cholesterol (HDL-C) levels were higher in two of the five transgenic rabbit lines than in controls (line 20 versus nontransgenic littermate, HDL-C = 80 +/- 7 versus 37 +/- 6 mg/dL; line 8 versus nontransgenic littermate, HDL-C = 54 +/- 16 versus 35 +/- 6 mg/dL). This resulted in less atherogenic lipoprotein profiles, with very low (VLDL + LDL-C)/HDL-C ratios. HDL size and protein and lipid compositions were similar between transgenic and littermate nontransgenic rabbits. However, a large amount of pre-beta apo A-I-containing lipoproteins was observed in the plasma of the highest human apo A-I expressor. Cell cholesterol efflux was evaluated with the incubation of whole serum from transgenic and control rabbits. Cell cholesterol efflux was highly correlated with HDL cholesterol, with apo A-I, and with the presence of pre-beta apo A-I-containing lipoproteins. These rabbits will be an extremely useful model for the evaluation of the effect of increased hepatic apo A-I expression on atherosclerosis.

Animals↗