Atherosclerosis Regression and Cholesterol Efflux in Hypertriglyceridemic Mice.

Rationale: Hypertriglyceridemia (HyperTG) and low high-density lipoprotein cholesterol (HDL-C), both of which are regulated by lipoprotein lipase (LpL) activity, associate with increased cardiovascular disease (CVD). Genetic regulators of LpL actions track with CVD risk in humans. Whether this is due to changes in HDL-C or function, or circulating triglyceride (TG) levels is unresolved. Objective: We created HyperTG and HDL-C reduction in atherosclerotic mice to allow the assessment of how HyperTG and reduced HDL-C affect regression of atherosclerosis and the phenotype of plaque macrophages. Methods and Results: Atherosclerosis regression was studied in control LpL floxed (Lplfl/fl) mice and tamoxifen-inducible whole-body LpL KO (iLpl-/-) mice with HyperTG (~500mg/dL) and reduced HDL-C (~50% reduction). Atherosclerosis regression was studied using two models in which advanced plaques resulting from hypercholesterolemia are exposed to normal LDL-C levels using aortic transplantation or treatments with oligonucleotides. In a subset of mice, we expressed human cholesterol ester transfer protein (hCETP) to humanize the relationship between apoB-lipoproteins and HDL. HDL particle number (HDL-P), cholesterol efflux capacity (CEC) and HDL proteome were measured in HyperTG mice and humans. Surprisingly, HyperTG and reduced HDL-C levels due to loss of LpL did not affect atherosclerosis lesion size or macrophage content (CD68+ cells) in either model. Expression of hCETP and further reduction of HDL-C did not alter lesions. Sera from iLpl-/- mice had a decrease in total CEC, but not ABCA1-mediated CEC. HyperTG humans, including those with LpL deficiency, had greater ABCA1-mediated CEC and total CEC per HDL-P. Conclusions: Atherosclerosis regression in mice is driven by LDL-C reduction and is not affected by HyperTG and plasma HDL-C levels.