Induction of fatal inflammation in LDL receptor and ApoA-I double-knockout mice fed dietary fat and cholesterol

Atherogenic response to dietary fat and cholesterol challenge was evaluated in mice lacking both the 11)L receptor (LDLr-/-) and apoA-I (apoA-I-/-) gene, IDLr-/-/apoA-I-/- or double-knockout mice. Gender- and age-matched LDLr-/-/apoA-I-/- mice were fed a diet consisting of 0.1% cholesterol and 10% palm oil for 16 weeks and compared to IDLr-/- mice or single-knockout mice. The LDLr-/- mice showed a 6- to 7-fold increase in total plasma cholesterol (TPC) compared to their chow-fed mice counterparts, while LDLr-/-/apoA-I-/- mice showed only a 2- to 3-fold increase in TPC compared to their chow-fed controls. This differential response to the atherogenic diet was unanticipated, since chow-fed LDLr-/- and LDLr-/-/ apoA-I-/- mice began the study with similar LDL levels and differed primarily in their HDL concentration. The 6-fold diet-induced increase in TPC observed in the LDLr-/- mice occurred mainly in VLDL/LDL and not in HDL. Mid-study plasma samples taken after 8 weeks of diet feeding showed that LDLr-/- mice had TPC concentrations. approximately 60% of their 16-week level, while the IDLr-/-/apoA-I-/- mice had reached 100% of their 16-week TPC concentration after only 8 weeks of diet. Male IDLr-/- mice showed similar aortic cholesterol levels to male LDLr-/-/ apoA-I-/- mice despite a 4-fold higher VLDL/LDL concentration in the LDLr-/- mice. A direct comparison of the severity of aortic atherosclerosis between female LDLr-/- and LDLr-/-/apoA-I-/- mice was compromised due to the loss of female LDLr-/-/apoA-I(-/-)mice between 10 and 14 weeks into the study. Diet-fed female and, with time, male LDLr-/-/apoA-I-/- mice suffered from severe ulcerated cutaneous xanthomatosis. This condition, combined with a complete de-pletion of adrenal cholesterol, manifested in fatal wasting of the affected mice. In conclusion, LDLr-/- and IDLr-/-/apoA-I-/- mice showed dramatic TPC differences in response to dietary fat and cholesterol challenge, while despite these differences both genotypes accumulated similar levels of aortic cholesterol.