GENETIC-DIETARY REGULATION OF SERUM PARAOXONASE EXPRESSION AND ITS ROLE IN ATHEROGENESIS IN A MOUSE MODEL

In an effort to identify genetic factors contributing to atherogenesis , we have studied inbred strains of mice that are susceptible (C57BL/6 J) and resistant (C3H/HeJ) to diet-induced aortic fatty streak lesions , When maintained on a low-fat diet, HDL isolated from both strain C57 BL/6J (B6) and C3H/HeJ (C3H) mice protect against LDL oxidation in a c oculture model of the artery wall. However, when maintained on an athe rogenic diet high in fat and cholesterol, the HDL isolated from B6 mic e lose the capacity to protect, whereas HDL from C3H mice protect equa lly well, Associated with the loss in the ability of HDL to protect is a decrease in the activity of serum paraoxonase, a serum esterase car ried on HDL that has previously been shown to protect against LDL oxid ation in vitro, The levels of paraoxonase mRNA decreased in B6 mice up on challenge with the atherogenic diet but increased in C3H, indicatin g that paraoxonase production is under genetic control, In a set of re combinant inbred strains derived from the B6 and C3H parental strains, low paraoxonase mRNA levels segregated with aortic lesion development , supporting a role for paraoxonase in atherogenesis.