TRANSGENIC MICE THAT OVEREXPRESS MOUSE APOLIPOPROTEIN-B - EVIDENCE THAT THE DNA-SEQUENCES CONTROLLING INTESTINAL EXPRESSION OF THE APOLIPOPROTEIN-B GENE ARE DISTANT FROM THE STRUCTURAL GENE

An 87-kilobase (kb) P1 bacteriophage clone (p649) spanning the mouse a polipoprotein (apo) B gene was used to generate transgenic mice that e xpress high levels of mouse apoB. Plasma levels of apoB, low density l ipoprotein cholesterol, and low density lipoprotein triglycerides were increased, and high density lipoprotein cholesterol levels were decre ased in the transgenic mice, compared with nontransgenic littermate co ntrols. Although p649 contained 33 kb of 5'-flanking sequences and 11 kb of 3'-flanking sequences, the tissue pattern of transgene expressio n was different from that of the endogenous apoB gene. RNA slot blots and RNase protection analysis indicated that the transgene was express ed in the liver but not in the intestine, whereas the endogenous apoB gene was expressed in both tissues. To confirm the absence of transgen e expression in the intestine, the mouse apoB transgenic mice were mat ed with the apoB knockout mice, and transgenic mice that were homozygo us for the apoB knockout mutation were obtained. Because of the absenc e of transgene expression in the intestine, those mice lacked all inte stinal apoB synthesis, resulting in a marked accumulation of fats with in the intestinal villus enterocytes. The current studies, along with prior studies of human apoB transgenic animals, strongly suggest that the DNA sequence element(s) controlling intestinal expression of the a poB gene is located many kilobases from the structural gene.