Abstract 13168: Total Lipoprotein Lipase Deficiency Does Not Impact Atherosclerosis Development in Low Density Lipoprotein Receptor Deficient Mice

Abstract

Introduction: Elevated LDL cholesterol (LDL-C) is a major causal factor for CVD. However, the importance of elevated triglyceride rich lipoproteins (TRLs) on CVD is still being investigated. Lipoprotein lipase (LpL) is the rate limiting enzyme hydrolyzing circulating very low density lipoprotein (VLDL) and chylomicrons. The effect of increased TRLs as an independent factor on atherosclerosis is not known, in part, because hypertriglyceridemia associates with low levels of LDL-C. Objective: We tested whether whole body LpL deficiency in mice combined with LDL receptor (LDLR) deficiency and an atherogenic diet affects lesion formation. Hypothesis: LpL deficient mice will not show increased atherosclerosis progression as compared to control mice, despite severe dyslipidemia, due to reduced infiltration of atherogenic lipids into the aortic endothelium. Methods: Induced global LpL deficiency (i Lpl -/- ) was created by tamoxifen injection to activate beta actin-driven cre. To knock down hepatic LDLR we utilized anti sense oligonucleotides (ASOs) as well as a PCSK9 expressing AAV. Results: i Lpl -/- mice on chow diet have elevated plasma triglycerides, increased VLDL cholesterol, lower LDL-C and lower high density lipoprotein cholesterol (HDL-C) compared to control Lpl fl/fl mice. However, when hepatic LDLR was knocked down with using LDLR ASO or AAV PCSK9, iLpl -/- mice displayed elevated LDL-C of about 150 mg/dl, similar to the levels seen in control mice with LDLR knockdown. When i Lpl -/- mice were fed an atherogenic Western diet for 16 weeks, i Lpl -/- mice developed severe hypertriglyceridemia (1500-8000 mg/dl) and increased total cholesterol to ~1500 mg/dl. LDL-C levels were similar to those of control mice with LDLR knockdown; ~200 mg/dl. HDL-C was lower in i Lpl -/- mice compared to the controls (~10 mg/dl vs ~30 mg/dl). i Lpl -/- mice had slightly smaller lesions in brachiocephalic arteries but macrophage content was similar to the controls. Aortic root lesion size was similar in both groups of mice. Conclusion: Despite severe hypertriglyceridemia, hypercholesterolemia and low HDL-C, iLpL -/- mice did not exhibit altered atherosclerosis progression, likely because of the absence of LpL-derived atherogenic lipids or remnant lipoproteins.