Abstract Body: Hypertriglyceridemia is increasingly recognized as a key driver of endothelial activation and atherosclerosis. We recently reported that hypertriglyceridemia caused by induced global lipoprotein lipase-deficiency (iLpl^-/-) trigger endothelial inflammatory signatures and accelerated aortic plaque development in LDL receptor knockout (Ldlr^-/-) mice, underscoring the pathogenic role of nascent triglyceride (TG)-rich lipoproteins (TRLs) in vascular disease. We also showed that a protein fragment comprising the N-terminal 18% of apolipoprotein B100 (ApoB18) blocks endothelial cell uptake of chylomicrons. In this study, we investigated the effects of liver-targeted adeno-associated virus (AAV)-mediated expression of ApoB18 (TBG-AAV8-ApoB18) on vascular inflammation in Ldlr^-/- and iLpl^-/-/Ldlr^-/- mice following 12 weeks of Western diet feeding. An empty TBG-AAV8 was used as control. Compared with Ldlr^-/- mice, iLpl^-/-/Ldlr^-/- mice exhibited markedly elevated circulating TG levels (1193 mg/dL vs. 264 mg/dL; n=14). Single-cell RNA-sequencing of the aorta (n=4) revealed robust upregulation of inflammatory genes, including Thbs1, Vcam1, Icam1, Tgfb1, Nfkb1, Klf2, and Klf4 in endothelial cells, macrophages, and smooth muscle cells, indicating widespread vascular inflammation in iLpl^-/-/Ldlr^-/- mice compared with Ldlr^-/- mice. Pathway enrichment analysis further demonstrated that global LPL-deficiency elevated multiple pro-atherogenic and inflammatory signaling networks, including lipid and atherosclerosis pathways as well as MAPK signaling, consistent with an enhanced cellular response to dysregulated lipid metabolism. TBG-AAV8-ApoB18 treatment attenuated the expression of these inflammatory genes in both genotypes. Assessment of circulating ApoB18 showed that this protein was expressed at a molar ratio of less than 10% of both lipoprotein ApoB100 and ApoB48 and in vitro competition studies confirmed that this fragment appeared to be a better ligand for both scavenger receptor BI and activin-like kinase 1 than lipoprotein-associated ApoB , since competition with ApoB18 at a molar ratio as low as 1% significantly inhibited EC uptake of both LDL (48.2% uptake compared to control, p<0.0001) and chylomicrons (42.3% uptake compared to control, p<0.0001). These findings demonstrate that AAV-mediated ApoB18 expression attenuates vascular inflammation, with likely implications for atherosclerosis enhanced by endothelial cell uptake of ApoB-containing lipoproteins.