Lipoprotein analysis in transgenic mice expressing human apolipoprotein (apo) A-I and apo C III: use of micromethods in analysis of lipoprotein system in mice.

Transgenic animal technology has added a new dimension to the study of lipoprotein physiology. The unique advantage of the technology is that the exact physiological role (s) of a gene and the corresponding protein whose function (s) has been undefined may be revealed in vivo by the expression or inactivation of the expression of the gene. Although mice are most frequently used transgenic animals, the lipoprotein system has not been studies extensively. This report primarily focuses on practical applications of the existing laboratory methods to transgenic mice expressing human apoproteins. Described below is the summary of the results obtained from transgenic mice expressing human apo A-I and apo C III. In one line of transgenic mice expressing human apo A-I, the total plasma apo A-I level (mouse plus human) was higher than that in control (mean +/- SEM, 381 +/- 18 vs. 153 +/- 7 mg/dl, n = 6, respectively, p = 0.0001) with 64% increase in the HDL cholesterol (HDL-C) level (90 +/- 3 vs. 55 +/- 5 mg/dl, p = 0.0001). High fat feeding further increased the apo A-I and HDL-C levels. One line of apo C III transgenic mice with approximately 100 copies of human apo C III gene were severely hypertriglyceridemic compared to negative littermates (mean +/- SEM; 959 +/- 217 vs. 49 +/- 6 mg/dl). In a second line, animals with one to two copies of the human apo C III gene manifested mild hypertriglyceridemia. These experiments revealed for the first time in vivo that overexpression of apo A-I and C III could lead respectively to hyperalphalipoproteinemia and hypertriglyceridemia and may suggest possible etiology for these disorders in human.