A marriage of mice produces answers to old questions about man
✍ Scribed by Allan Cooper
- Publisher
- John Wiley and Sons
- Year
- 1994
- Tongue
- English
- Weight
- 396 KB
- Volume
- 20
- Category
- Article
- ISSN
- 0270-9139
No coin nor oath required. For personal study only.
✦ Synopsis
The atherogenic macromolecule lipoprotein( a) [Lp(a) J has resisted in uiuo analyses partly because it is found in a limited number of experimental animals. Although transgenic mice expressing human apolipoprotein (a) [ape( a)] have previously been described, they failed to assemble Lp(a) particles because of the inability of human apo(a) to associate with mouse apolipoprotein B (apoB). We isolated a 90-kilobase P1 phagemid containing the human apoB gene and with this DNA generated 13 lines of transgenic mice of which 11 expressed human apoB. The human apoB transcript was expressed and edited in the liver of the transgenic mice. Plasma concentrations of human apoB, as well as low density lipoprotein (LDL), were related to transgene copy number; the transgenic line with the most copies of human apoB had a >4-fold increase in LDL cholesterol compared with nontransgenics and a lipoprotein profile similar to that of humans. When human apoB and apo(a) transgenic mice were bred together, plasma apo(a) in mice expressing both human proteins was tightly associated with lipoproteins in the LDL density region. These studies demonstrate the successful expression of human apoB and the efficient assembly of Lp(a) in mice.
COMMENTS
Like many other diseases, atherosclerosis is probably the pathologic end stage brought about by a variety of derangements of normal physiology. Several of the metabolic disturbances that eventually lead to atherosclerosis begin with disordered hepatic lipid and lipoprotein metabolism. One might even argue that the regulation of lipoprotein metabolism is the most complex and highly differentiated of liver functions (1). Atherosclerosis is a disease that occurs spontaneously only in human beings, and there are numerous differences in lipoprotein metabolism among species. There-