Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E‐related disorders in humans

Abstract

Apolipoprotein E (apo E) deficiency (or its abnormalities in humans) is associated with a series of pathological conditions including dyslipidemia, atherosclerosis, Alzheimer's disease, and shorter life span. The purpose of this study was to characterize these conditions in apo E-deficient C57BL/6J mice and relate them to human disorders. Deletion of apo E gene in mice is associated with changes in lipoprotein metabolism [plasma total cholesterol (TC) (>+400%), HDL cholesterol (-80%), HDL/TC, and HDL/LDL ratios (-93% and -96%, respectively), esterification rate in apo B-depleted plasma (+100%), plasma triglyceride (+200%), hepatic HMG-CoA reductase activity (-50%), hepatic cholesterol content (+30%)], decreased plasma homocyst(e)ine and glucose levels, and severe atherosclerosis and cutaneous xanthomatosis. Hepatic and lipoprotein lipase activities, hepatic LDL receptor function, and organ antioxidant capacity remain unchanged. Several histological/immunohistological stainings failed to detect potential markers for neurodegenerative disease in the brain of 37-wk-old male apo E-KO mice. Apo E-KO mice may have normal growth and development, but advanced atherosclerosis and xanthomatosis may indirectly reduce their life span. Apo E plays a crucial role in regulation of lipid metabolism and atherogenesis without affecting lipase activities, endogenous antioxidant capacity, or appearance of neurodegenerative markers in 37-wk-old male mice.

Amelioration of Renal Ischemia–Reperfusion Injury by Inhibition of IL-6 Production in the Poloxamer 407–Induced Mouse Model of Hyperlipidemia

“…In addition, we recently observed that treatment of mice with pravastatin, another HMGCoA reductase inhibitor, or L-744832, a farnesyl transferase inhibitor, improved renal I/R injury and inhibited the injury-induced increase in plasma IL-6 concentration (12). Since HMG-CoA reductase activity has been suggested to be low in hyperlipidemic mice in comparison with that in normolipidemic mice (13,14,28,29), lower activity of HMG-CoA reductase may be associated with attenuated production of IL-6 in hyperlipidemic mice.…”

Impact of environmental factors on alloimmunity and transplant fate

“…Several murine models of altered plasma lipids have been developed for the study of atherosclerosis, including apolipoprotein E-deficient (ApoE-deficient) mice (42). Feeding ApoE-deficient mice an HFD increased serum cholesterol (42)(43)(44)(45), although these mice did not become obese or hyperglycemic, making it possible to study the effects of high plasma lipid levels without other confounding comorbidities that have independent effects on immunity (46,47).…”

Sharing and specificity of co-expression networks across 35 human tissues

“…For example, the genes which increased most in hubness in the two skin tissues were APOE, which has been linked with skin lesions known as xanthomas [40] (although it is more famous because of its link with Alzheimer's) and CERS3 [41], which when mutated causes congenital ichthyosis, a skin disease. Similarly, in the testis, the top-two ranked tissue-specific hubs were DDX3Y and KDM5D, both Y-chromosome linked genes which function in spermatogenesis [42][43][44].…”