Location: Obesity and Metabolism ResearchTitle: Real time magnetic resonance imaging of apo AI metabolism in vivo) Author
|Van Loan, Marta|
Submitted to: Journal of American Chemists Society
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/31/2010
Publication Date: 1/24/2011
Publication URL: onlinelibrary.wiley.com/doi/10.1002/nbm.1650/pdf
Citation: Sriram, R., Iagerstedt, J.O., Samardzic, H., Kreutzer, U., Kaysen, G., Voss, J., Desreux, J.F., Thonon, D., Jacques, V., Van Loan, M.D. 2011. Real time Magnetic Resonance Imaging of Apo AI Metabolism In Vivo. Journal of American Chemists Society. 10.1002/nbm.1650. Interpretive Summary: Metabolism of blood lipids or fat in the blood stream, also known as lipoproteins, is a key indicator of cardiovascular disease risk. Metabolism of lipopoteins follows complex pathways and a key component in high density lipoprotein (HDL) is Apolipoprotien AI (apo AI), synthesized in the liver and small intestine. Ultimately Apo AI and HDL bind together to take up cholesterol. Because of this critical role to scavenge cholesterol, low Apo AI and low HDL cholesterol are good prognostic indicators of high risk for cardiovascular disease. Therefore, we developed a magnetic resonance imaging (MRI) contrast agent to image the real time distribution of APO AI in a mouse model.
Technical Abstract: Apolipoprotein AI (apo AI) plays a key role in maintaining cardiovascular health and constitutes the major lipoprotein component in high density lipoproteins (HDL). It metabolism, however, follows a complex pathway. Synthesized in the liver and intestines, its becomes lipidated by its interaction with the ATP binding cassette-1 transporter (ABCA-1) to form discoidal HDL and takes up cholesterol, which licithin:cholesterol acyltransferase (LCAT) esterifies to remodel HDL into its spherical form. HDL continues to interact with receptor B type 1 (SR B1) receptor to facilitate a net cholesterol efflux from the cell. Because of its critical cholesterol scavenging activity, low apo A1 and HDL levels predict a high cardiovascular risk. In obesity, diabetes, chronic kidney disease (CKD), the decreased HDL level arises from increased clearance rather than decreased synthesis. Cardiovascular disease leads as the major cause of death. In particular, HDL fails to mature properly, secondary to a decreased LCAT activity, in dialysis patients. These small dense HDL particles clear rapidly through increased glomerular filtration followed by renal proximal tubule uptake and catabolism. However, the site of increased HDL disposal in renal failure is unknown. The deficiency in HDL maturation points to an altered metabolic regulation, most notably in depressed LCAT activity or apo AI synthesis. Observing apo A1 biodistribution in vivo yields insight into the complex metabolic regulation affecting a range of physiologiocal conditions. We have developed a magnetic resonance image (MRI) contrast agent which links Gd-methanethiosulfonate (Gd (MTS-DOTA) to a single Cys mutation in apo AI and have imaged in real time the distribution of apo A1 in a mouse model.