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Trimerized apolipoprotein A-I TripA forms lipoproteins, activates lecithincholesterol acyltransferase, elicits lipid efflux, and is transported through aortic endothelial cells



Trimerized apolipoprotein A-I TripA forms lipoproteins, activates lecithincholesterol acyltransferase, elicits lipid efflux, and is transported through aortic endothelial cells



Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1811(12): 0-1123



Apolipoprotein A I (apoA-I) exerts many potentially anti-atherogenic properties and is therefore attractive for prevention and therapy of coronary heart disease. Since induction of apoA-I production by small molecules has turned out as difficult, application of exogenous apoA-I is pursued as an alternative therapeutic option. To counteract fast renal filtration of apoA-I, a trimeric high-molecular weight variant of apoA-I (TripA) was produced by recombinant technology. We compared TripA and apoA-I for important properties in reverse cholesterol transport. Reconstituted high-density lipoproteins (rHDL) containing TripA or apoA-I together with palmitoyl-2-oleyl-phosphatidylcholine (POPC) differed slightly by size. Compared to apoA-I, TripA activated lecithin:cholesterol acyltransferase (LCAT) with similar maximal velocity but concentration leading to half maximal velocity was slightly reduced (Km = 2.1 .3 ?g/ml vs.59 .6 ?g/ml). Both in the lipid-free form and as part of rHDL, TripA elicited cholesterol efflux from THP1-derived macrophages with similar kinetic parameters and response to liver-X-receptor activation as apoA-I. Lipid-free TripA is bound and transported by aortic endothelial cells through mechanisms which are competed by apoA-I and TripA and inhibited by knock-down of ATP-binding cassette transporter (ABC) APre-formed TripA/POPC particles were bound and transported by endothelial cells through mechanisms which are competed by excess native HDL as well as reconstituted HDL containing either apoA-I or TripA and which involve ABCG1 and scavenger receptor B1 (SR-BI). In conclusion, apoA-I and TripA show similarin vitroproperties which are important for reverse cholesterol transport. These findings are important for further development of TripA as an anti-atherosclerotic drug.Important properties of a potentially therapeutic mimetic of apoA-I, the trimeric apoA-I variant TripA, were analyzed. TripA activated LCAT with similar maximal velocity but slightly reduced affinity compared to apoA-I. Both in the lipid-free and lipidated form, TripA elicited cholesterol efflux from macrophages. Lipid-free and lipidated TripA is bound and transported by endothelial cells by mechanisms comparable to apoA-I and HDL. In conclusion, apoA-I and TripA show similar in vitroproperties which are important for reverse cholesterol transport..

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Accession: 036204362

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DOI: 10.1016/j.bbalip.2011.09.001


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