Expression of human apolipoprotein A-II in apolipoprotein E-deficient miceinduces features of familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is a common inherited hyperlipidemi a and a major risk factor for atherothrombotic cardiovascular disease. The cause(s) leading to FCHL are largely unknown, but the existence of unidenti fied "major" genes that would increase VLDL production and of "modifier" ge nes that would influence the phenotype of the disease has been proposed. Ex pression of apolipoprotein A-II (apoA-II), a high density lipoprotein (HDL) of unknown function, in transgenic mice produced increased concentration o f apoB-containing lipoproteins and decreased HDL, Here we show that express ion of human apoA-II in apoE-deficient mice induces a dose-dependent increa se 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 normoli pidemic humans, as tr ell as other well-known characteristics of FCHL: incr eased concentrations of cholesterol, triglyceride, and apoB in very low den sity lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low den sity 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 apoB-de ficient mice overexpressing human apoA-II, and the apoA-II gene has not bee n 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 in dividuals through unkown mechanisms including an action on a "major" FCHL g ene.jlr We conclude that apoE-deficient mice overexpressing human apoA-II c onstitute useful animal models with which to study the mechanisms leading t o overproduction of VLDL, and that apoA-II may function to regulate VLDL pr oduction.