Expression of human apolipoprotein A-I/C-III/A-IV gene cluster in mice induces hyperlipidemia but reduces atherogenesis

The apolipoprotein (apo)A-I/C-III/A-IV gene cluster is involved in lipid me tabolism and atherosclerosis. Overexpression of apoC-III in mice causes hyp ertriglyceridemia and induces atherogenesis, whereas overexpression of apoA -I or apoA-IV increases cholesterol in plasma high density lipoprotein (HDL ) and protects against atherosclerosis. Each gene has been studied alone in transgenic mice but not in combination as the entire cluster. To determine which phenotype is produced by the expression of the entire gene cluster, transgenic mice were generated with a 33-kb human DNA fragment. The results showed that the transgene contained the necessary elements to direct hepat ic and intestinal expression of the 3 genes. In the pooled data, plasma con centrations were 257+/-9, 7.1+/-0.5, and 1.0+/-0.2 mg/dL for human apoA-I, apoC-III, and apoA-IV, respectively (meant SEM). Concentrations of these ap olipoproteins were higher in males than in females. Human apoA-I and apoC-I II concentrations were positively correlated, suggesting that they are core gulated, Transgenic mice exhibited gross hypertriglyceridemia and accumulat ion of apoB(48)-containing triglyceride-rich lipoproteins, Plasma triglycer ide and cholesterol concentrations were correlated positively with human ap oC-III concentration, and HDL cholesterol was correlated with apoA-I concen tration. In an apoE-deficient background, despite being markedly hypertrigl yceridemic, cluster transgenic animals compared with nontransgenic animals showed a 61% reduction in atherosclerosis. This suggests that apoA-I and/or apoA-IV can protect against atherosclerosis even in the presence of severe hyperlipidemia. These mice provide a new model for studies of the regulati on of the 3 human genes in combination.