VLDL best predicts aortic root atherosclerosis in LDL receptor deficient mice

Abstract

Hyperlipidemia is a major risk factor for developing atherosclerosis in humans, and epidemiological studies have correlated specific lipoprotein levels with cardiovascular disease risk. Murine models of atherosclerosis rely on the induction of hyperlipidemia for vascular lesions to form, but the pathogenic contributions attributed to different lipoprotein populations are not well defined. To address this issue, we analyzed over 300 LDL receptor (LDLR) deficient mice that have been fed a high-fat diet and for which a full lipoprotein profile and aortic root atherosclerosis values were assessed. Overall, aortic root atherosclerosis is best predicted by plasma VLDL cholesterol levels with less predictive value derived from either LDL or HDL cholesterol. Triglyceride levels are more atherogenic in female mice, especially immune competent females, and depletion of the adaptive immune system leads to a global reduction in plasma lipid levels and aortic root lesion size yet does not appear to alter the atherogenic potential of individual lipoprotein subspecies. In contrast, HDL-cholesterol is a better predictor of aortic root atherosclerosis in apoE-deficient mice. In summary, this large scale analysis of high-fat diet fed LDLR deficient mice highlight the relationship between different plasma lipid components, especially VLDLcholesterol, and aortic root atherosclerosis.-VanderLaan, P. A., C. A. Reardon, R. A. Thisted, and G. S. Getz. VLDL best predicts aortic root atherosclerosis in LDL receptor deficient mice. J. Lipid Res. 2009. 50: 376-385. Supplementary key words hyperlipidemia • cholesterol • HDL Atherosclerosis is a vascular site-specific chronic inflammation initiated in response to retained and modified lipids within the arterial wall that can eventually lead to clinically significant endpoints including myocardial infarction, peripheral arterial disease, and stroke (1-3). Although multiple risk factors have been shown to play a significant role in the pathogenesis of atherosclerosis and cardiovascular disease, the determination of plasma lipid levels in humans remains a cornerstone in the clinical assessment of cardiovascular risk. Numerous large-scale epidemiological studies and clinical trials have associated different plasma lipid components with the risk for experiencing future cardiovascular events, with most focusing on total cholesterol, LDL cholesterol, and HDL cholesterol (4-10). These population-based studies and related trials of lipid-lowering agents (especially concerning the statin class of drugs) have firmly established that hypercholesterolemia is a primary and treatable cause of atherosclerosis and cardiovascular disease in humans.Over the past 20 years, mouse models of atherosclerosis have proven extremely useful in dissecting the cellular and molecular interactions involved in atherogenesis. An almost uniform requirement for these models to develop vascular lesions is the induction of hypercholesterolemia, either through dietary or genetic means (11). It has not been shown wheth...

Dietary herring improves plasma lipid profiles and reduces atherosclerosis in obese low-density lipoprotein receptor-deficient mice

“…The differences in plasma lipid profile were consistent with lower amount of aortic arch plaques in the herring-fed mice compared with the beef-fed mice. The findings are in agreement the finding that plaque size in male Ldlr -/-mice was positively correlated to plasma TAG and VLDL-cholesterol concentrations, and negatively to plasma HDL-cholesterol concentrations (33). The question is which bioactive compounds are present in herring but not in beef that could mediate such effects and by which mechanisms?…”

In vivo activation of leukocyte GPR120/FFAR4 by PUFAs has minimal impact on atherosclerosis in LDL receptor knockout mice

“…First, inflammation, while important in the initiation and progression of atherosclerosis, likely plays a less important role in the LDLrKO mouse model, in which apoB lipoproteins are elevated in plasma. Past studies from our laboratory and others have shown that atherosclerosis is highly associated with plasma VLDL cholesterol concentrations in LDLrKO mice (31,48) and leukocyte GPR120/FFAR4 expression did not affect plasma VLDL concentrations in our study. Thus, the elevation of plasma VLDL likely overwhelmed any beneficial effect of BM GPR120/FFAR4 expression in our study.…”

Update on the Role of Endothelial Lipase in High-Density Lipoprotein Metabolism, Reverse Cholesterol Transport, and Atherosclerosis

“…Although there are conflicting results regarding EL's pro-or antiatherogenic functions, speculation is raised that vascular EL, particularly at the site of atherosclerotic lesions, may accelerate the process of atherosclerosis in apoE −/− mice, 57 whereas elevation of the VLDL fraction affected by hepatic EL deficiency might be crucial for developing atherosclerosis in LDLR −/− mice. 64 These findings might explain the result that EL deficiency reduces atherosclerosis against the apoE knockout background, but not the LDLR knockout background.…”