Trimerized apolipoprotein A-I (TripA) forms lipoproteins, activates lecithin: cholesterol acyltransferase, elicits lipid efflux, and is transported through aortic endothelial cells

Biochim Biophys Acta. 2011 Dec;1811(12):1115-23. doi: 10.1016/j.bbalip.2011.09.001. Epub 2011 Sep 10.


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 (K(m)=2.1±0.3μg/mL vs. 0.59±0.06μg/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) A1. Pre-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 similar in vitro properties which are important for reverse cholesterol transport. These findings are important for further development of TripA as an anti-atherosclerotic drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Aorta / cytology
  • Aorta / drug effects
  • Aorta / metabolism
  • Apolipoprotein A-I / chemistry
  • Apolipoprotein A-I / metabolism*
  • Apolipoprotein A-I / pharmacology
  • Atherosclerosis / drug therapy
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Cardiovascular Agents / chemistry
  • Cardiovascular Agents / metabolism*
  • Cardiovascular Agents / pharmacology
  • Cattle
  • Coronary Disease / drug therapy
  • Coronary Disease / metabolism*
  • Coronary Disease / pathology
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism*
  • Gene Silencing
  • Humans
  • Kinetics
  • Lipoproteins, HDL / chemistry
  • Lipoproteins, HDL / metabolism
  • Phosphatidylcholine-Sterol O-Acyltransferase / metabolism
  • Phosphatidylcholines / metabolism
  • Protein Binding
  • Protein Transport / drug effects
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism*
  • Recombinant Proteins / pharmacology


  • ATP-Binding Cassette Transporters
  • Apolipoprotein A-I
  • Cardiovascular Agents
  • Lipoproteins, HDL
  • Phosphatidylcholines
  • RNA, Small Interfering
  • Recombinant Proteins
  • Phosphatidylcholine-Sterol O-Acyltransferase