Familial combined hyperlipidemia (FCHL) is a common inherited hyperlipidemia and a major risk factor for atherothrombotic cardiovascular disease. The cause(s) leading to FCHL are largely unknown, but the existence of unidentified 'major' genes that would increase VLDL production and of 'modifier' genes that would influence the phenotype of the disease has been proposed. Expression of apolipoprotein A-II (apoA-II), a high density lipoprotein (HDL) of unknown function, in transgenic mice produced increased concentration of apoB-containing lipoproteins and decreased HDL. Here we show that expression of human apoA-II in apoE-deficient mice induces a dose-dependent increase in VLDL, resulting in plasma triglyceride elevations of up to 24-fold in a mouse line that has 2-fold the concentration of human apoA-II of normolipidemic humans, as well as other well-known characteristics of FCHL: increased concentrations of cholesterol, triglyceride, and apoB in very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL), reduced HDL cholesterol, normal lipoprotein lipase and hepatic lipase activities, increased production of VLDL triglycerides, and increased susceptibility to atherosclerosis. However, FCHL patients do not have plasma concentrations of human apoA-II as high as those of apo.E-deficient mice overexpressing human apoA-II, and the apoA-II gene has not been linked to FCHL in genome-wide scans. Therefore, the apoA-II gene could be a 'modifier' FCHL gene influencing the phenotype of the disease in some individuals through unkown mechanisms including an action on a 'major' FCHL gene. We conclude that apoE-deficient mice over-expressing human apoA-II constitute useful animal models with which to study the mechanisms leading to overproduction of VLDL, and that apoA-II may function to regulate VLDL production.
|Journal||Journal of Lipid Research|
|Publication status||Published - 13 Sep 2000|
- High density lipoprotein
- Transgenic mice
- Very low density lipoprotein
Escolà-Gil, J. C., Julve, J., Marzal-Casacuberta, À., Ordóñez-Llanos, J., González-Sastre, F., & Blanco-Vaca, F. (2000). Expression of human apolipoprotein A-II apolipoprotein E-deficient mice induces features of familial combined hyperlipidemia. Journal of Lipid Research, 41(8), 1328-1338.