Effectiveness and safety of dupilumab in the treatment of atopic dermatitis in children (6-11 years): data from a French multicentre retrospective cohort in daily practice.

BACKGROUND: Dupilumab is the first biotherapy available for the treatment of moderate-to-severe childhood atopic dermatitis (AD). OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety of dupilumab in daily practice. METHODS: Patients aged 6-11, who had received a first dose of dupilumab, were included in this multicentre retrospective cohort study. The primary endpoint was change in SCORAD after 3 months of treatment. Secondary endpoints were change in IGA score at 3 months, proportion of patients with SCORAD50 and SCORAD75, description of adverse events and proportion of children in our cohort who would be excluded from pivotal phase 3 clinical trial. RESULTS: Eighty patients were included. After 3 months of treatment, there was a significant decrease in SCORAD (mean: 21.8 ± 13.8 vs 53.9 ± 18.5; P < 0.0001) and IGA (1.3 ± 0.8 vs 3.5 ± 0.7; P < 0.0001). Conjunctivitis was observed in 11.3% (n = 9/80); three patients experienced dupilumab facial redness (DFR); 17.5% (n = 14/80) reported injection site reactions; 6.3% (n = 5/80) discontinued treatment. 61.2% (n = 49/80) children were ineligible in the phase 3 trial. LIMITATIONS: There is no control group. Because it was a real life study based on information from patient medical records in a French multicentre cohort, we cannot rule out the presence of reporting bias generated by the use of patient reported characteristics and missing information. CONCLUSION: These real-life data confirm the efficacy and safety of dupilumab in children with moderate to severe AD extended to dyshidrosis and atopic prurigo, but it also revealed a lower frequency of DFR and conjunctivitis. However, administration in injectable form may be a barrier in this age group.

Liver X receptor modulators: effects on lipid metabolism and potential use in the treatment of atherosclerosis.

Liver X receptors (LXRs) are nuclear receptors that play a crucial role in regulating the expression of genes involved in lipid metabolism. Ligand activation of LXRs improves cholesterol homeostasis via multiple coordinated effects, and this function is likely to explain in part the protective effects of LXR activation on atherosclerosis reported in animal models. However, LXR activation may also induce undesirable side effects, such as lipogenesis and hypertriglyceridemia. This review discusses the potential to develop LXR modulators as therapeutic agents for atherosclerosis.

Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice.

Excess tissue glucocorticoid action may underlie the dyslipidemia, insulin resistance, and impaired glucose tolerance of the metabolic syndrome. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyzes conversion of circulating inert 11-dehydrocorticosterone into active corticosterone, thus amplifying local intracellular glucocorticoid action, particularly in liver. The importance of 11beta-HSD-1 in glucose homeostasis is suggested by the resistance of 11beta-HSD-1(-/-) mice to hyperglycemia upon stress or obesity, due to attenuated gluconeogenic responses. The present study further investigates the metabolic consequences of 11beta-HSD-1 deficiency, focusing on the lipid and lipoprotein profile. Ad lib fed 11beta-HSD-1(-/-) mice have markedly lower plasma triglyceride levels. This appears to be driven by increased hepatic expression of enzymes of fat catabolism (carnitine palmitoyltransferase-I, acyl-CoA oxidase, and uncoupling protein-2) and their coordinating transcription factor, peroxisome proliferator-activated receptor-alpha (PPARalpha). 11beta-HSD-1(-/-) mice also have increased HDL cholesterol, with elevated liver mRNA and serum levels of apolipoprotein AI. Conversely, liver Aalpha-fibrinogen mRNA levels are decreased. Upon fasting, the normal elevation of peroxisome proliferator-activated receptor-alpha mRNA is lost in 11beta-HSD-1(-/-) mice, consistent with attenuated glucocorticoid induction. Despite this, crucial oxidative responses to fasting are maintained; carnitine palmitoyltransferase-I induction and glucose levels are similar to wild type. Refeeding shows exaggerated induction of genes encoding lipogenic enzymes and a more marked suppression of genes for fat catabolism in 11beta-HSD-1(-/-) mice, implying increased liver insulin sensitivity. Concordant with this, 24-h refed 11beta-HSD-1(-/-) mice have higher triglyceride but lower glucose levels. Further, 11beta-HSD-1(-/-) mice have improved glucose tolerance. These data suggest that 11beta-HSD-1 deficiency produces an improved lipid profile, hepatic insulin sensitization, and a potentially atheroprotective phenotype.

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.

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.

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.

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.

Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor.

A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can lead to the development of atherosclerosis, a disease influenced by both systemic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E -/- mice, a well established animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome proliferator-activated receptor (PPAR)gamma and a dual agonist of both PPARalpha and PPARgamma had moderate inhibitory effects. Both RXR and liver X receptor (LXR) agonists induced ATP-binding cassette protein 1 (ABC-1) expression and stimulated ABC-1-mediated cholesterol efflux from macrophages from wild-type, but not from LXRalpha and beta double -/-, mice. Hence, activation of ABC-1-mediated cholesterol efflux by the RXR/LXR heterodimer might contribute to the beneficial effects of rexinoids on atherosclerosis and warrant further evaluation of RXR/LXR agonists in prevention and treatment of atherosclerosis.

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.

Transcriptional regulation of apolipoprotein C-III gene expression by the orphan nuclear receptor RORalpha.

Triglyceride-rich remnant lipoproteins are considered as major risk factors contributing to the pathogenesis of atherosclerosis. Because apolipoprotein (apo) C-III is a major determinant of plasma triglyceride and remnant lipoprotein metabolism, it is important to understand how the expression of this gene is regulated. In the present study, we identified the orphan nuclear receptor RORalpha1 as a regulator of human and mouse apo C-III gene expression. Plasma triglyceride and apo C-III protein concentrations in staggerer (sg/sg) mice, homozygous for a deletion in the RORalpha gene, were significantly lower than in wild type littermates. The lowered plasma apo C-III levels were associated with reduced apo C-III mRNA levels in liver and intestine of sg/sg mice. Transient transfection experiments in human hepatoma HepG2, human colonic CaCO2, and rabbit kidney RK13 cells demonstrated that overexpression of the human RORalpha1 isoform specifically increases human apo C-III promoter activity, indicating that RORalpha1 enhances human apo C-III gene transcription. RORalpha1 response elements were mapped by promoter deletion analysis and gel shift experiments to two AGGTCA half-sites located at positions -83/-78 (within the C3P site) and -23/-18 (downstream of the TATA box) in the human apo C-III promoter, with the -23/-18 site exhibiting the highest binding affinity. Transfection of site-directed mutated constructs in HepG2 cells indicated that the RORalpha1 effect is predominantly mediated by the -23/-18 site. This site is conserved in the mouse apo C-III gene promoter. Moreover, RORalpha binds to the equivalent mouse site and activates constructs containing three copies of the mouse site cloned in front of an heterologous promoter. Taken together, our data identify RORalpha as a transcriptional regulator of apo C-III gene expression, providing a novel, physiological role for RORalpha1 in the regulation of genes controlling triglyceride metabolism.

Decreased susceptibility to diet-induced atherosclerosis in human apolipoprotein A-II transgenic mice.

Studies performed in vivo have been controversial regarding the implication of human apolipoprotein (apo)A-II in the atherogenic process. Expression of human apoA-II in transgenic mice fed a chow diet leads to (1) a bimodal distribution of high density lipoprotein (HDL) size as in humans, (2) a reduction in total cholesterol concentration that is mainly due to a reduction in non-HDL cholesterol level, and (3) a dramatic reduction in mouse endogenous apoA-I and apoA-II. After 20 weeks on an atherogenic diet, transgenic mice had reduced total cholesterol concentrations because of a reduction in cholesterol associated with all lipoprotein classes. Endogenous apoA-I and apoA-II were also dramatically decreased in transgenic mice. The mean area of atherosclerotic lesions was drastically decreased in transgenic mice (-44%, P=0.0027) compared with control mice. The amount of aortic surface covered by lesions was positively correlated with very low density lipoprotein cholesterol (P<0.01) and intermediate density lipoprotein cholesterol levels (P<0.05). Transgenic mice were protected against the development of atherosclerosis despite a marked decrease in HDL cholesterol and apoA-I concentrations. This protection may be related to the marked reduction in circulating low density lipoprotein (very low density and intermediate density lipoprotein) levels in transgenic mice.

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.

Activation of PPARdelta alters lipid metabolism in db/db mice.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements in the promoters of regulated genes. Despite the wealth of information available on the function of PPARalpha and PPARgamma, relatively little is known about the most widely expressed PPAR subtype, PPARdelta. Here we show that treatment of insulin resistant db/db mice with the PPARdelta agonist L-165041, at doses that had no effect on either glucose or triglycerides, raised total plasma cholesterol concentrations. The increased cholesterol was primarily associated with high density lipoprotein (HDL) particles, as shown by fast protein liquid chromatography analysis. These data were corroborated by the chemical analysis of the lipoproteins isolated by ultracentrifugation, demonstrating that treatment with L-165041 produced an increase in circulating HDL without major changes in very low or low density lipoproteins. White adipose tissue lipoprotein lipase activity was reduced following treatment with the PPARdelta ligand, but was increased by a PPARgamma agonist. These data suggest both that PPARdelta is involved in the regulation of cholesterol metabolism in db/db mice and that PPARdelta ligands could potentially have therapeutic value.

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.

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.

3-Hydroxy-3-methylglutaryl CoA reductase inhibitors reduce serum triglyceride levels through modulation of apolipoprotein C-III and lipoprotein lipase.

Statins are hypolipidemic drugs which not only improve cholesterol but also triglyceride levels. Whereas their cholesterol-reducing effect involves inhibition of de novo biosynthesis of cellular cholesterol through competitive inhibition of its rate-limiting enzyme 3-hydroxy-3-methylglutaryl CoA reductase, the mechanism by which they lower triglycerides remains unknown and forms the subject of the current study. Treatment of normal rats for 4 days with simvastatin decreased serum triglycerides significantly, whereas it increased high density lipoprotein cholesterol moderately. The decrease in triglyceride concentrations after simvastatin was caused by a reduction in the amount of very low density lipoprotein particles which were of an unchanged lipid composition. Simvastatin administration increased the lipoprotein lipase mRNA and activity in adipose tissue and heart. This effect on lipoprotein lipase was accompanied by decreased mRNA as well as plasma levels of the lipoprotein lipase inhibitor apolipoprotein C-III. These results suggest that the triglyceride-lowering effect of statins involves a stimulation of lipoprotein lipase-mediated clearance of triglyceride-rich lipoproteins.

Beneficial effects of fibrates on apolipoprotein A-I metabolism occur independently of any peroxisome proliferative response.

BACKGROUND: In humans, fibrates are frequently used normolipidemic drugs. Fibrates act by regulating genes involved in lipoprotein metabolism via activation of the peroxisome proliferator-activated receptor-alpha (PPARalpha) in liver. In rodents, however, fibrates induce a peroxisome proliferation, leading to hepatomegaly and possibly hepatocarcinogenesis. Although this peroxisome proliferative response appears not to occur in humans, it remains controversial whether the beneficial effects of fibrates on lipoprotein metabolism can occur dissociated from such undesirable peroxisomal response. Here, we assessed the influence of fenofibrate on lipoprotein metabolism and peroxisome proliferation in the rabbit, an animal that, contrary to rodents and similar to humans, is less sensitive to peroxisome proliferators. METHODS AND RESULTS: First, we demonstrate that in normal rabbits, fenofibrate given at a high dose for 2 weeks does not influence serum concentrations or intestinal mRNA levels of the HDL apolipoprotein apoA-I. Therefore, the study was continued with human apoA-I transgenic rabbits that overexpress the human apoA-I gene under control of its homologous promoter, including its PPAR-response elements. In these animals, fenofibrate increases serum human apoA-I concentrations via an increased expression of the human apoA-I gene in liver. Interestingly, liver weight or mRNA levels and activity of fatty acyl-CoA oxidase, a rate-limiting and marker enzyme of peroxisomal beta-oxidation, remain unchanged after fenofibrate. CONCLUSIONS: Expression of the human apoA-I transgene in rabbit liver suffices to confer fibrate-mediated induction of serum apoA-I. Furthermore, these data provide in vivo evidence that the beneficial effects of fibrates on lipoprotein metabolism occur mechanistically dissociated from any deleterious activity on peroxisome proliferation and possibly hepatocarcinogenesis.

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.