title: Induction of fatal inflammation in LDL receptor and ApoA-I double-knockout mice fed dietary fat and cholesterol.
abstract: 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.
authors.affiliation: Department of Pathology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Manal
authors.initials: M
authors.lastname: Zabalawi
authors.forename: Shaila
authors.initials: S
authors.lastname: Bhat
authors.forename: Tara
authors.initials: T
authors.lastname: Loughlin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.forename: Eric
authors.initials: E
authors.lastname: Alexander
authors.forename: Mark
authors.initials: M
authors.lastname: Cline
authors.forename: Bill
authors.initials: B
authors.lastname: Bullock
authors.forename: Mark
authors.initials: M
authors.lastname: Willingham
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sorci-Thomas
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001018:Aortic Diseases / Q000209:etiology* / Q000401:mortality; D016632:Apolipoprotein A-I / Q000172:deficiency*; D001053:Apolipoproteins / Q000097:blood; D001161:Arteriosclerosis / Q000209:etiology* / Q000401:mortality; D002784:Cholesterol / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000009:adverse effects*; D004041:Dietary Fats / Q000009:adverse effects*; D005260:Female; D007249:Inflammation / Q000209:etiology / Q000401:mortality; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011537:Pruritus / Q000209:etiology; D011973:Receptors, LDL / Q000172:deficiency*; D012727:Sex Characteristics; D012871:Skin Diseases / Q000209:etiology; D013997:Time Factors; D014973:Xanthomatosis / Q000209:etiology
chemical_list: D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D008055:Lipids; D008074:Lipoproteins; D011973:Receptors, LDL; D002784:Cholesterol