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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.
Insights
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.
Abstract:
Familial HDL deficiencies are associated with variable susceptibility to premature coronary heart disease, but the mechanism underlying this association remains poorly understood. Three homozygotes with isolated complete apo A-I deficiency caused by an autosomal codominant apo A-I Q[-2]X mutation and one heterozygote developed coronary heart disease before age 40 years. We characterized the effects of this mutation on lipoprotein metabolism. LDL FC, phospholipid, and apo B were all significantly higher in homozygotes than in heterozygotes. The HDLs of the heterozygotes were apo A-I poor relative to apo A-II. Lecithin-cholesterol acyltransferase activity was 59% lower in homozygotes than in normal subjects or heterozygotes. Cholesteryl ester transfer activity was increased in a homozygote compared with a normolipidemic control subject. Postprandial lipid metabolism was studied in one homozygote and one heterozygote. Post-prandial TG response in the homozygote was significantly exaggerated, while residual plasma HDL level remained unaffected. The homozygote also had delayed clearance of retinyl ester, a marker of chylomicron remnant metabolism. Thus, homozygosity and heterozygosity for apo A-I Q[-2]X are associated with qualitative, as well as quantitative, disturbances in plasma HDLs, LDLs, lipid-modifying enzyme activities, and postprandial retinyl ester metabolism. The observed elevation of atherogenic lipoproteins and reduction in antiatherogenic lipoproteins in the affected members of the apo A-I Q[-2]X kindred are consistent with the primary deficiency in apo A-I having pleiotropic effects that markedly enhance susceptibility for coronary heart disease.