Abstract 508: Combined Lipoprotein Lipase And Ldl Receptor Deficiency Increases Atherosclerosis: Hyperchylomicronemia Is Not Benign

Abstract

We tested whether accumulation of chylomicrons as an addition to LDL would enhance atherosclerosis. To do this, whole body LpL deficiency was combined with LDL receptor (LDLR) deficiency. Induced global LpL deficiency (i Lpl -/- ) was created by tamoxifen injections to activate beta actin-driven cre recombinase in mice. To knock down hepatic LDLR we utilized anti-sense oligonucleotides (ASOs) or a PCSK9 expressing AAV. i Lpl -/- mice on chow diet have elevated plasma TGs, increased VLDL cholesterol, and lower LDL-C compared to control Lpl fl/fl mice. In contrast, when hepatic LDLR was knocked down, the mice displayed elevated LDL-C (~150 mg/dl), similar to the levels seen in control mice with LDLR knockdown. i Lpl -/- mice fed a Western diet for 12 weeks developed severe hypertriglyceridemia (1400-7000 mg/dl) and increased total cholesterol reaching ~1500 mg/dl. LDL-C levels were lower in iLpL -/- mice (160 mg/dl vs 359 mg/dl) and the increase in cholesterol was primarily in chylomicrons compared to the control mice with LDLR knockdown (1064 mg/dl vs 238 mg/dl). i Lpl -/- mice had bigger lesions in the brachiocephalic artery (46000 um 2 vs 13000 um 2 ) but macrophage content was lower than the control LDLR-deficient mice (24% vs 69%). Aortic root lesion size was larger (60000 um 2 vs 26000 um 2 ), due to a greater the percentage of collagen (34% vs 23%), but not macrophages (60% vs 58%) or neutral lipid content (34% vs 35%). The lack of differences in macrophage accumulation and neutral lipid content and the increase in the collagen content indicates an advanced lesion in the iLpl -/- mice. Thus, our data suggest that intact chylomicrons contribute to atherosclerosis.