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(American Journal of Pathology. 2003;163:1201-1213.)
© 2003 American Society for Investigative Pathology

Animal Model

Induction of Fatal Inflammation in LDL Receptor and ApoA-I Double-Knockout Mice Fed Dietary Fat and Cholesterol

Manal Zabalawi^*, Shaila Bhat^*, Tara Loughlin^*, Michael J. Thomas, Eric Alexander^*, Mark Cline^*, Bill Bullock^*, Mark Willingham^* and Mary G. Sorci-Thomas^*

From the Departments of Pathology^* and Biochemistry, Wake Forest University Health Sciences, Winston-Salem, North Carolina

Atherogenic response to dietary fat and cholesterol challenge was evaluated in mice lacking both the LDL receptor (LDLr^-/-) and apoA-I (apoA-I^-/-) gene, LDLr^-/-/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 LDLr^-/- 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 LDLr^-/-/apoA-I^-/- mice had reached 100% of their 16-week TPC concentration after only 8 weeks of diet. Male LDLr^-/- 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 depletion of adrenal cholesterol, manifested in fatal wasting of the affected mice. In conclusion, LDLr^-/- and LDLr^-/-/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.

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