Risk Stratification of Apolipoprotein B, Apolipoprotein A1, and Apolipoprotein B/AI Ratio on the Prevalence of the Metabolic Syndrome: the ATTICA Stud

First Cardiology Clinic, School of Medicine, University of Athens, Greece

We investigated the association of apolipoproteins AI and B in relation to the prevalence of metabolic syndrome in a random sample of cardiovascular disease— free adults from the ATTICA study (1,514 men, aged 18-87 y; 1,528 women, aged 18-89 y). Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The prevalence of metabolic syndrome was 25% in men and 15% in women (P < .001). Using the area under the Receiver Operation Characteristic curve, apolipoprotein B/AI was the best diagnostic marker of metabolic syndrome, the optimal discriminating cut-off value of this ratio was 0.72 (sensitivity 74%, specificity 67%), and individuals with apolipoprotein B/AI ratio greater than 0.74 had 3.29 times higher odds of having metabolic syndrome (95% confidence interval: 2.56-4.21) after adjusting for potential confounders.

Treatment with an apolipoprotein A-1 mimetic peptide in combination with pravastatin inhibits collagen-induced arthritis

To evaluate the therapeutic potential of an apolipoprotein A-1 (apoA-1) mimetic peptide, D-4F, in combination with pravastatin in collagen-induced arthritis (CIA), syngeneic Louvain rats were immunized with type II collagen and randomized to vehicle control, D-4F monotherapy, pravastatin monotherapy, or D-4F + pravastatin combination therapy. Clinical arthritis activity was evaluated and radiographs, type II collagen antibody titers, cytokine/chemokine levels, and HDL function analysis were obtained. There was significant reduction in clinical severity scores in the high and medium dose D-4F + pravastatin groups compared to controls (p ≤ 0.0001). Reduction in erosive disease occurred in the medium/high dose combination groups compared to non-combination groups (p ≤ 0.01). Favorable changes in cytokines/chemokines were noted with treatment, and response to combination D-4F/pravastatin therapy was associated with improvement in HDL's anti-inflammatory properties. Combination D-4F/pravastatin significantly reduced clinical disease activity in CIA, and may have dual therapeutic potential in other autoimmune diseases with increased cardiovascular morbidity and mortality.


ARTICLE

Lipidation of apolipoprotein A-I by ATP-binding cassette transporter (ABC) A1 generates an interaction partner for ABCG1 but not for scavenger recepto

The ATP-binding cassette transporters ABCA1 and ABCG1 as well as scavenger receptor BI (SR-BI) mediate the efflux of lipids from macrophages to apolipoprotein A-I (apoA-I) and high density lipoproteins (HDL). We used RNA interference in RAW264.7 macrophages to study the interactions of ABCA1, ABCG1, and SR-BI with lipid-free apoA-I, native and reconstituted HDL with apoA-I:phosphatidylcholine ratios of either 1:40 (rHDL1:40) or 1:100 (rHDL1:100). Knock-down of ABCA1 inhibits the cellular binding at 4 °C of lipid-free apolipoprotein A-I (apoA-I) but not of HDL whereas suppression of ABCG1 or SR-BI reduces the binding of high density lipoproteins (HDL). but not lipid-free apoA-I. The degree of lipidation influences the interactions of rHDL with ABCG1 and SR-BI. Knock-down of ABCG1 inhibits more effectively the binding and cholesterol efflux capacities of lipid-poorer rHDL1:40 whereas knock-down of SR-BI has a more profound effect on the binding and cholesterol efflux capacities of lipid-richer rHDL1:100. Moreover, knock-down of ABCG1 but not SR-BI interferes with the association of lipid-free apoA-I during prolonged incubation at 37 °C. Finally, knock-down of ABCG1 inhibits the binding of initially lipid-free apoA-I which has been preconditioned by cells with high ABCA1 activity. The gained ability of initially lipid-free apolipoprotein A-I (apoA-I) to interact with ABCG1 is accompanied by its shift from electrophoretic pre-β- to -mobility. Taken together, these data suggest that the interaction of lipid-free apoA-I with ABCA1 generates a particle that immediately interacts with ABCG1 but not with SR-BI. Furthermore, the degree of lipidation influences the interaction of HDL with ABCG1 or SR-BI.

Iris Lorenzia, Arnold von Eckardsteina, Silvija Radosavljevica and Lucia Rohrer

ARTICLE

Low diurnal variability of apolipoprotein A1, apolipoprotein B and apolipoprotein B/apolipoprotein A1 ratio during normal sleep and after an acute shi

Objective
The aim of this study was to study the diurnal variation of the cardiovascular risk markers apolipoprotein A1 and B and apo B/apo A1 ratio.

Design and methods
We have studied the diurnal variation of apolipoprotein A1, apolipoprotein B and apo B/apo A1 ratio during night sleep and the day sleep conditions in seven healthy volunteers (age 22–32 yr). Samples were collected every hour to evaluate the effect of different sampling times on the test results.

Results
The lowest diurnal coefficient of variation (CV) was observed for the apo B/apo A1 ratio, which usually was below 2% but also apolipoprotein A1, apolipoprotein B showed low CV. There were no significant differences between nightsleep and daysleep for any of the studied markers.

Conclusion
Even if there was a diurnal variation for these markers, the variation was very low. Thus, sampling does not have to be restricted to certain times of the day.

ARTICLE

Rosuvastatin selectively stimulates apolipoprotein A-I but not apolipoprotein A-II synthesis in Hep G2 cells

Hydroxymethylglutaryl–coenzyme A reductase inhibitors (statins) are extensively used to regulate dyslipidemia and to reduce atherosclerotic cardiovascular disease. In addition to effectively lowering cholesterol and low-density lipoprotein (HDL) levels, rosuvastatin and certain other statins can also increase plasma high-density lipoprotein (HDL) cholesterol modestly. However, the mechanism of action of rosuvastatin on HDL metabolic processes is not understood. Using cultured human hepatoblastoma cells (Hep G2) as an in vitro model system, we assessed the effect of rosuvastatin on apolipoprotein (apo) A-I and apo A-II (the major proteins of HDL) synthesis and HDL catabolic processes. Rosuvastatin dose-dependently increased messenger RNA expression and de novo synthesis of apo A-I but not apo A-II. Rosuvastatin selectively increased the synthesis of HDL particles containing only apo A-I (LP A-I) but not particles containing both apo A-I and A-II (LP A-I + A-II). The HDL3-protein or HDL3-cholesterol ester uptake by Hep G2 cells was not affected by rosuvastatin. The apo A-I–containing particles secreted by rosuvastatin-treated Hep G2 significantly increased cholesterol efflux from fibroblasts. The data indicate that rosuvastatin increases hepatic apo A-I but not apo A-II messenger RNA transcription, thereby selectively increasing the synthesis of functionally active apo A-I–containing HDL particles, which mediate cholesterol efflux from peripheral tissues. We suggest that this mechanism of action of rosuvastatin to increase apo A-I production without apo A-I/HDL removal may result in increased apo A-I turnover that results in accelerated reverse cholesterol transport.

Shucun Qina, b, Takafumi Kogaa, b, Shobha H. Ganjia, b, Vaijinath S. Kamanna, a, b, and Moti L. Kashyap

ARTICLE

Cholesterol is a determinant of the structures of discoidal high density lipoproteins formed by the solubilization of phospholipid membranes by apolip

Formation of discoidal high density lipoproteins(rHDL) by Apolipoprotein A-I (apoA-I) mediated solubilization of dimyristoyl phosphatidylcholine (DMPC) multilamellar vesicles (MLV) was dramatically affected by bilayer cholesterol concentration. At a low ratio of DMPC/apoA-I (2 mg DMPC/mg apoA-I, 84/1 mol/mol), sterols (cholesterol, lathosterol, and β-sitosterol) that form ordered lipid phases increase the rate of solubilization similarly, yielding rHDL with similar structures. By changing the temperature and sterol concentration, the rates of solubilization varied almost 3 orders of magnitude; however, the sizes of the rHDL were independent of the rate of their formation and dependent upon the bilayer sterol concentration. At a high ratio of DMPC/apoA-I (10/1 mg DMPC/mg apoA-I, 420/1 mol/mol), changing the temperature and cholesterol concentration yielded rHDL that varied greatly in size, phospholipid/protein ratio, mol% cholesterol, and number of apoA-I molecules per particle. rHDL were isolated that had 2, 4, 6, and 8 molecules of apoA-I per particle, mean diameters of 117, 200, 303, and 396 Å, and a mol% cholesterol that was similar to the original MLV. Kinetic studies demonstrated that the different sized rHDL are formed independently and concurrently. The rate of formation, lipid composition, and three-dimensional structures of cholesterol-rich rHDL is dictated primarily by the original membrane phase properties and cholesterol content. The size speciation of rHDL and probably nascent HDL formed via the activity of the ABCA1 lipid transporter is mechanistically linked to the cholesterol content of the membranes from which they were formed.

Keywords: Reverse cholesterol transport; apoA-I; Cholesterol; High density lipoprotein; Phosphatidylcholine; Microsolubilization

John B. Massey, a, and Henry J. Pownall

ARTICLE

An apolipoprotein A-I gene promoter polymorphism associated with cognitive decline, but not with Alzheimer's disease.

BACKGROUND/AIMS: Accumulating biological and epidemiological evidence suggests a close link between cholesterol metabolism and the pathophysiology of Alzheimer's disease (AD).

The observation that the use of statins reduces the risk of Alzheimer's disease sustains this hypothesis. Apolipoprotein A-I (APOA1) is the major component of the high-density lipoproteins , particles involved in reverse cholesterol transport. Therefore, genetic polymorphisms in the gene encoding APOA1 might influence cholesterol metabolism and be a risk factor for AD.

A previous study suggested an impact of a G-->A polymorphism at position -75 bp in the APOA1 gene on the risk for early-onset AD and on the age at onset of the disease. We studied this polymorphism in 3 independent European population samples. METHODS: Genotyping was conducted asdescribed in the previous study.

RESULTS: We were unable to show any impact of this polymorphism on the risk of AD. Conversely, subjects bearing the A allele of this polymorphism were at risk of cognitive decline. CONCLUSION: Our resultssuggest an impact of the G-->A polymorphism at position -75 bp in the APOA1 gene on cognitive impairment, but not on the risk of AD. Copyright (c) 2007 S. Karger AG, Basel.

Helbecque N, Codron V, Cottel D, Amouyel P.
INSERM, U744, Institut Pasteur de Lille, Université de Lille 2, Lille, France.
Dement Geriatr Cogn Disord. 2008;25(2):97-102. Epub 2007 Dec 10