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J. Biol. Chem., Vol. 278, Issue 7, 4740-4746, February 14, 2003

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Targeted Replacement of Mouse Apolipoprotein A-I with Human ApoA-I or the Mutant ApoA-I_Milano
EVIDENCE OF APOA-I_M IMPAIRED HEPATIC SECRETION^*

Cinzia Parolini^§, Giulia Chiesa, Yiwen Zhu^¶, Trudy Forte^¶, Silvia Caligari, Elisabetta Gianazza, Maria Grazia Sacco, Cesare R. Sirtori, and Edward M. Rubin^¶

From the  Department of Pharmacological Sciences, University of Milan, 20133 Milan, Italy,  Istituto di Tecnologie Biomediche-Consiglio Nazionale delle Ricerche, 20090 Segrate, Milan, Italy, the ^¶ Genome Sciences Department, Lawrence Berkeley National Laboratory, Berkeley, California 94720

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.

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