Apolipoprotein Mimetic Peptides for Stimulating Cholesterol Efflux

2015 ◽  
pp. 29-42 ◽  
Author(s):  
Dan Li ◽  
Scott Gordon ◽  
Anna Schwendeman ◽  
Alan T. Remaley
Keyword(s):  
Cholesterol Efflux ◽  
Mimetic Peptides

We-W38:1 The role of various structural motifs of HDL-mimetic peptides in cholesterol efflux by the ABCA1 transporter

2006 ◽  
Vol 7 (3) ◽  
pp. 320
Author(s):  
A.T. Remaley ◽  
J. Stonik ◽  
T. Fairwell ◽  
S. Demosky ◽  
E.B. Neufeld ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Structural Motifs ◽  
Mimetic Peptides

The Promise of Apolipoprotein AI-Based Therapy

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Trusca VG
Keyword(s):  
Gene Expression ◽  
Amino Acids ◽  
Cholesterol Efflux ◽  
Regulatory Elements ◽  
Environmental Chemicals ◽  
Atherogenic Dyslipidemia ◽  
Oral Drug ◽  
High Density Lipoproteins ◽  
Atherosclerotic Plaques ◽  
Mimetic Peptides

Apolipoprotein A-I (ApoAI) is an anti-atherosclerotic protein that promotes cholesterol efflux from tissues to the liver for excretion [1]. ApoAI is the main structural and functional protein of High- Density Lipoproteins (HDL), representing ~70% of total HDL proteins [2,3]. Circulating apoAI protein is an amphipathic protein (28kDa) comprising eight alpha-helical domains of 22 amino acids and two repeats of 11 amino acids [4]. Consequently, ApoAI binds avidly to lipids and readily moves between lipoprotein particles; however, ~5-10% of human plasma ApoAI exists in a free state (lipoprotein-unbound) [5]. ApoAI protein is more than a structural scaffold that maintains lipid packaging, as it plays an important role in the transport of cellular cholesterol from the artery wall to the liver for catabolism [6-8]. Antioxidant and anti-inflammatory properties were also attributed to apoAI [9,10]. In addition, a protective role of apoAI against cancer was proposed [11]. ApoAI is synthesized mainly in the liver and small intestine and there are a lot of regulatory elements and transcription factors that control apoAI gene expression, as reviewed in [12]. Treatment with BPA (bisphenol A), one of the most widespread environmental chemicals, downregulates ApoAI gene expression, aggravating the atherosclerotic plaques in LDLR-/- mice [13]. Interestingly, the ratio of HDL-cholesterol to apoAI protein levels is an indicator of the risk of the cardiovascular disorder [14]. Lack of ApoAI augmented atherosclerosis in various hypercholesterolemic mice, such as mice expressing human apoB or ApoAI-/-/LDLR-/- mice [15,16]. In humans, familial ApoAI deficiency is associated with premature coronary heart disease [17]. Interestingly, low levels of apoAI and atherogenic dyslipidemia were found in obese individuals, but increases in apoAI levels and enhancements of cholesterol efflux capacity of HDL were reported at three months after bariatric surgery [18]. Considering the anti-atherogenic properties of apoAI, various apoAI-based therapies were proposed for reduction of atherogenesis: i) overexpression of ApoAI, ii) infusions of ApoAI protein, ApoAI mimetic peptides, or ApoAI-containing HDL [19-21], iii) oral small molecules that stimulate ApoAI production [22]. Overexpression of ApoAI reduced atherogenesis in apoE-/- or LDLR-/- atherosclerotic mice [23-31]. Infusions of ApoAI mimetic peptides led to the regression of aortic valve stenosis in rabbits [32]. Liver-directed adenoviral gene transfer of ApoAI resulted in the regression of preexisting atheroma in LDLR-/- mice [33]. Undoubtedly, local delivery of apoAI protein to the vascular wall represents a more efficient apoAIbased therapy than its systemic delivery. Remarkably, transduction of vascular endothelial cells with ApoAI expressing adenovirus reduced inflammation and protected against atherosclerosis in hyperlipidemic rabbits [34,35]. The oral drug RVX-208 significantly increased apoAI production in monkeys but presented disappointing efficacy in a phase II trial [36]. Notwithstanding there are good results obtained in studies using animal models, several apoAI-based clinical trials failed to regress atherosclerotic plaques in humans [37,38]. Despite tremendous advances regarding the understanding of apoAI, the promise of apoAI-based therapy awaits new studies and trials.

Abstract 626: The ABCA1 Agonist Peptides CS-6253 and ATI-5261 Replicate ApoA-I Function and Generate nHDL Particles that Are Remodeled and Maturated Within the Plasma Compartment, Resulting in Efficient Cholesterol SR-BI Delivery to Hepatic Cells

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Anouar Hafiane ◽  
John Bielicki ◽  
Jan Johansson ◽  
Jacques Genest
Keyword(s):  
Cholesterol Efflux ◽  
Plasma Lipoproteins ◽  
Hepatic Tissue ◽  
Lipid Transfer ◽  
Hepatic Cells ◽  
Mimetic Peptides ◽  
Esterification Rate ◽  
Fractional Esterification Rate ◽  
Plasma Compartment

Novel apolipoprotein (apo) mimetic peptides are potent mediators of ABCA1-mediated cholesterol efflux, mimicking native apoA-I. We investigated CS-6253 (CS) and ATI-5261 (ATI) in their ability to promote lipid transfer between nascent (n)HDL particles and plasma lipoproteins and examined cholesterol influx from remodelled HDL-like particles to hepatic cells through the SR-BI receptor. nHDL-like lipoproteins nHDL-CS and nHDL-ATI were generated by incubating CS or ATI in the presence of BHK cells expressing ABCA1 labelled with 3 [H]cholesterol and 3 [H] choline; native apoA-I was used as control. These nHDL particles were incubated with plasma at 37°C. Both CS and ATI increased LCAT activity significantly, although were approximately 50% less efficient than nHDL-apoA-I (fractional esterification rate (FER) =22.32±0.86%/h; vs nHDL-CS and nHDL-ATI; FER=11.40±0.045%/h; p<0.05). The majority of 3 [H]cholesterol from nHDL mimetics was esterified by LCAT, resulting in an increase in α1-migrating HDL-like particles in plasma (as shown by 2D-PAGGE). The ability of nHDL mimetics to transfer 3 [H]-phosphatidyl choline to plasma apoB-containing lipoproteins is (76±20%) in HDL-apoA-I, (38±0.5%) in nHDL-ATI and (54±13%) in nHDL-CS. These data show that nHDL mimetics are actively remodelled in the presence of plasma lipoproteins. We then investigated cholesterol delivery from HDL-CS and HDL-ATI mimetic to hepatic tissue via SR-BI using Fu5AH cells, having HDL-apoA-I as control. Kinetic parameters for SR-BI-mediated cholesterol influx are as follows: HDL-CS ( K m = 0.30±0.05 ug/ml; p<0.05) efficient as HDL apoA-I at promoting cholesterol uptake into Fu5AH cells ( K m = 0.37±0.13 ug/ml), while HDL-ATI was least efficient ( K m = 1.03±0.20 ug/ml). The inhibition of SR-BI selective uptake with BLT-1 affected the uptake of cholesterol from apoB precipitated plasma containing either HDL-CS, HDL-ATI or apoA-I. Here we present an in-vitro model of nHDL-CS and nHDL-ATI that actively undergo remodelling and maturation in plasma and replicate the function of apoA-I. These mature HDL mimetics generated from ABCA1 agonist peptides deliver cholesterol efficiently to hepatocytes specifically through the SR-BI receptor.

scholarly journals Structural properties of apolipoprotein A-I mimetic peptides that promote ABCA1-dependent cholesterol efflux

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Rafique M. Islam ◽  
Mohsen Pourmousa ◽  
Denis Sviridov ◽  
Scott M. Gordon ◽  
Edward B. Neufeld ◽  
...  
Keyword(s):  
Structural Properties ◽  
Cholesterol Efflux ◽  
Apolipoprotein A ◽  
Mimetic Peptides

scholarly journals Incorporation of α-methylated amino acids into Apolipoprotein A-I mimetic peptides improves their helicity and cholesterol efflux potential

2020 ◽  
Vol 526 (2) ◽  
pp. 349-354
Author(s):  
Rafique Islam ◽  
Denis O. Sviridov ◽  
Steven K. Drake ◽  
Jude Tunyi ◽  
Galina Abdoulaeva ◽  
...  
Keyword(s):  
Amino Acids ◽  
Cholesterol Efflux ◽  
Apolipoprotein A ◽  
Mimetic Peptides

The Anti-Atherogenic Properties of Sesamin are Mediated via Improved Macrophage Cholesterol Efflux Through PPARγ1-LXRα and MAPK Signaling

2014 ◽  
Vol 84 (1-2) ◽  
pp. 79-91 ◽  
Author(s):  
Amin F. Majdalawieh ◽  
Hyo-Sung Ro
Keyword(s):  
Cholesterol Efflux ◽  
Transcriptional Activity ◽  
Molecular Mechanisms ◽  
Foam Cell ◽  
Mapk Signaling ◽  
Luciferase Reporter ◽  
Foam Cell Formation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Macrophage Cholesterol Efflux

Background: Foam cell formation resulting from disrupted macrophage cholesterol efflux, which is triggered by PPARγ1 and LXRα, is a hallmark of atherosclerosis. Sesamin and sesame oil exert anti-atherogenic effects in vivo. However, the exact molecular mechanisms underlying such effects are not fully understood. Aim: This study examines the potential effects of sesamin (0, 25, 50, 75, 100 μM) on PPARγ1 and LXRα expression and transcriptional activity as well as macrophage cholesterol efflux. Methods: PPARγ1 and LXRα expression and transcriptional activity are assessed by luciferase reporter assays. Macrophage cholesterol efflux is evaluated by ApoAI-specific cholesterol efflux assays. Results: The 50 μM, 75 μM, and 100 μM concentrations of sesamin up-regulated the expression of PPARγ1 (p< 0.001, p < 0.001, p < 0.001, respectively) and LXRα (p = 0.002, p < 0.001, p < 0.001, respectively) in a concentration-dependent manner. Moreover, 75 μM and 100 μM concentrations of sesamin led to 5.2-fold (p < 0.001) and 6.0-fold (p<0.001) increases in PPAR transcriptional activity and 3.9-fold (p< 0.001) and 4.2-fold (p < 0.001) increases in LXR transcriptional activity, respectively, in a concentration- and time-dependent manner via MAPK signaling. Consistently, 50 μM, 75 μM, and 100 μM concentrations of sesamin improved macrophage cholesterol efflux by 2.7-fold (p < 0.001), 4.2-fold (p < 0.001), and 4.2-fold (p < 0.001), respectively, via MAPK signaling. Conclusion: Our findings shed light on the molecular mechanism(s) underlying sesamin’s anti-atherogenic effects, which seem to be due, at least in part, to its ability to up-regulate PPARγ1 and LXRα expression and transcriptional activity, improving macrophage cholesterol efflux. We anticipate that sesamin may be used as a therapeutic agent for treating atherosclerosis.

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