| First Author | Parolini C | Year | 2003 |
| Journal | J Biol Chem | Volume | 278 |
| Issue | 7 | Pages | 4740-6 |
| PubMed ID | 12471038 | Mgi Jnum | J:81908 |
| Mgi Id | MGI:2450215 | Doi | 10.1074/jbc.M207335200 |
| Citation | Parolini C, et al. (2003) Targeted replacement of mouse apolipoprotein A-I with human ApoA-I or the mutant ApoA-IMilano. Evidence of APOA-IM impaired hepatic secretion. J Biol Chem 278(7):4740-6 |
| abstractText | Despite a pro-atherogenic profile, individuals carrying the molecular variant (R173C) of apolipoprotein (apo)A-I, named apoA-I(Milano) (apoA-I(M)), appear to be at reduced risk for cardiovascular disease. To develop an in vivo system to explore, in a controlled manner, the effects of apoA-I(M) on lipid metabolism, we have used the gene targeting technology, or 'gene knock-in' (gene k-in), to replace the murine apoA-I gene with either human apoA-I or apoA-I(M) genes in embryonic stem cells. As in human carriers, mice expressing apoA-I(M) (A-I(M) k-in) are characterized by low concentrations of the human apolipoprotein and reduced high density lipoprotein cholesterol levels, compared with A-I k-in animals. The aim of the present study was to investigate the basic mechanisms of hypoalphalipoproteinemia associated with the apoA-I(M) mutation. ApoA-I and apoA-I(M) mRNA expression, as assessed by Northern blot analysis and quantitative real time reverse transcription-PCR, did not exhibit significant differences in either liver or intestine. Moreover, human apolipoprotein synthesis rates were similar in the k-in lines. When the secretion rate of the human apolipoproteins was assessed in cultured hepatocytes from the mouse lines, secretion from apoA-I(M)-expressing cells was markedly reduced (42% for A-I(M) k-in and 36% for A-I/A-I(M) k-in mice) as compared with that of A-I k-in hepatocytes. These results provide the first evidence that the hypoalphalipoproteinemia in apoA-I(M) human carriers may be partially explained by impaired apoA-I(M) secretion. |
