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Abstract
Using adenovirus‐mediated gene transfer in apolipoprotein A‐I (apoA‐I)‐deficient mice, we have established that apoA‐I mutations inhibit discrete steps in a pathway that leads to the biogenesis and remodeling of high‐density lipoprotein (HDL).
To this point, five discrete categories of apoA‐I mutants have been characterized that may affect the interactions of apoA‐I with ATP‐binding cassette superfamily A, member 1 (ABCA1) or lecithin:cholesterol acyl transferase (LCAT) or may influence the plasma phospholipid transfer protein activity or may cause various forms of dyslipidemia.
Biogenesis of HDL is not a unique property of apoA‐I. Using adenovirus‐mediated gene transfer of apoE in apoA‐I‐ or ABCA1‐deficient mice, we have established that apolipoprotein E (apoE) also participates in a novel pathway of biogenesis of apoE‐containing HDL particles. This process requires the functions of the ABCA1 lipid transporter and LCAT, and it is promoted by substitution of hydrophobic residues in the 261 to 269 region of apoE by Ala.
The apoE‐containing HDL particles formed in the circulation may have atheroprotective properties. ApoE‐containing HDL may also have important biological functions in the brain that confer protection from Alzheimer's disease.
| Abbreviations | ||
| ABCA1 | = | ATP‐binding cassette superfamily A, member 1 |
| ABCA1−/− | = | ABCA1‐deficient |
| apoA‐I | = | apolipoprotein A‐I |
| apoA‐I−/− | = | apoA‐I‐deficient mice |
| apoE | = | apolipoprotein E |
| apoE−/− | = | apoE‐deficient |
| ATP | = | adenosine triphosphate |
| cAMP | = | cyclic adenosine monophosphate |
| CE | = | cholesteryl esters |
| CETP | = | cholesteryl ester transfer protein |
| EM | = | electron microscopy |
| FPLC | = | fast pressure liquid chromatography |
| GFP | = | green fluorescence protein |
| HDL | = | high‐density lipoprotein |
| IDL | = | intermediate‐density lipoprotein |
| LCAT | = | lecithin:cholesterol acyl transferase |
| LDL | = | low‐density lipoprotein |
| pfu | = | plaque‐forming unit |
| PLTP | = | phospholipid transfer protein |
| SR‐BI | = | scavenger receptor class B type I |
| SR‐BI−/− | = | SR‐BI‐deficient |
| TC | = | total cholesterol |
| VLDL | = | very‐low‐density lipoprotein |
| WT | = | wild type |
| Abbreviations | ||
| ABCA1 | = | ATP‐binding cassette superfamily A, member 1 |
| ABCA1−/− | = | ABCA1‐deficient |
| apoA‐I | = | apolipoprotein A‐I |
| apoA‐I−/− | = | apoA‐I‐deficient mice |
| apoE | = | apolipoprotein E |
| apoE−/− | = | apoE‐deficient |
| ATP | = | adenosine triphosphate |
| cAMP | = | cyclic adenosine monophosphate |
| CE | = | cholesteryl esters |
| CETP | = | cholesteryl ester transfer protein |
| EM | = | electron microscopy |
| FPLC | = | fast pressure liquid chromatography |
| GFP | = | green fluorescence protein |
| HDL | = | high‐density lipoprotein |
| IDL | = | intermediate‐density lipoprotein |
| LCAT | = | lecithin:cholesterol acyl transferase |
| LDL | = | low‐density lipoprotein |
| pfu | = | plaque‐forming unit |
| PLTP | = | phospholipid transfer protein |
| SR‐BI | = | scavenger receptor class B type I |
| SR‐BI−/− | = | SR‐BI‐deficient |
| TC | = | total cholesterol |
| VLDL | = | very‐low‐density lipoprotein |
| WT | = | wild type |
Acknowledgements
This work was supported by grants from the National Institutes of Health (HL48739 and HL68216), the 6th Framework Programme of the European Union (No. LSHM‐CT‐2006‐0376331), and a grant from the American Heart Association (SDG 0535443T). Alexander Vezeridis is a trainee of the Predoctoral Training Grant in Cardiovascular Biology (T32 HL07969).