Targeted replacement of mouse apolipoprotein A-I with human ApoA-I or the mutant ApoA-IMilano. Evidence of APOA-IM impaired hepatic secretion
| Autor: | Parolini C, Chiesa G, Zhu Y, Forte T, Caligari S, Gianazza E, Sacco MG, Sirtori CR, Rubin EM. |
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| Rok vydání: | 2002 |
| Předmět: |
Apolipoprotein A-I
nutritional and metabolic diseases Hypolipoproteinemias Mice Gene Expression Regulation Liver Settore BIO/10 - Biochimica Mutation polycyclic compounds Settore BIO/14 - Farmacologia Animals Humans lipids (amino acids peptides and proteins) Intestinal Mucosa Lipoproteins HDL Cells Cultured |
| Zdroj: | 278 (2003): 4740–4746. info:cnr-pdr/source/autori:Parolini C, Chiesa G, Zhu Y, Forte T, Caligari S, Gianazza E, Sacco MG, Sirtori CR, Rubin EM./titolo:Targeted replacement of mouse apolipoprotein A-I with human ApoA-I or the mutant ApoA-IMilano. Evidence of APOA-IM impaired hepatic secretion./doi:/rivista:/anno:2003/pagina_da:4740/pagina_a:4746/intervallo_pagine:4740–4746/volume:278 |
| ISSN: | 0021-9258 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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