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Apolipoprotein A-I deficiency. Biochemical and metabolic characteristics
D S Ng1, C Vezina, T S Wolever
1Department of Medicine, St Michael's Hospital, University of Toronto, Ontario, Canada.
Arteriosclerosis, Thrombosis, and Vascular Biology
|December 1, 1995
Summary
Familial high-density lipoprotein (HDL) deficiencies due to apo A-I Q[-2]X mutations cause premature coronary heart disease. This mutation alters lipoprotein metabolism, increasing atherogenic lipoproteins and enhancing heart disease risk.
Area of Science:
- Cardiovascular Genetics
- Lipid Metabolism
- Molecular Medicine
Background:
- Familial high-density lipoprotein (HDL) deficiencies are linked to premature coronary heart disease (CHD).
- The precise mechanisms connecting HDL deficiencies to CHD susceptibility remain unclear.
- The apo A-I Q[-2]X mutation in apolipoprotein A-I (apo A-I) causes isolated complete apo A-I deficiency.
Purpose of the Study:
- To investigate the impact of the apo A-I Q[-2]X mutation on lipoprotein metabolism.
- To understand how this mutation contributes to premature coronary heart disease.
- To characterize the qualitative and quantitative disturbances in lipoprotein profiles and enzyme activities.
Main Methods:
- Studied three homozygotes and one heterozygote with the apo A-I Q[-2]X mutation.
- Analyzed low-density lipoprotein (LDL) composition, HDL particle content (apo A-I vs. apo A-II), and lecithin-cholesterol acyltransferase (LCAT) activity.
- Assessed cholesteryl ester transfer protein (CETP) activity and postprandial lipid metabolism, including triglyceride (TG) response and retinyl ester clearance.
Main Results:
- Homozygotes exhibited significantly higher LDL levels (FC, phospholipid, apo B) compared to heterozygotes.
- Heterozygotes showed HDL particles poor in apo A-I relative to apo A-II.
- LCAT activity was markedly reduced (59%) in homozygotes; CETP activity was increased in one homozygote. Postprandial studies revealed an exaggerated TG response and delayed retinyl ester clearance in the homozygote.
Conclusions:
- The apo A-I Q[-2]X mutation leads to significant disturbances in HDL and LDL metabolism, affecting enzyme activities and postprandial lipid handling.
- These metabolic alterations, including elevated atherogenic and reduced antiatherogenic lipoproteins, are consistent with increased susceptibility to coronary heart disease.
- The findings highlight the pleiotropic effects of apo A-I deficiency in enhancing cardiovascular risk.