Abstract 3043: Apolipoprotein A5 Alters The VLDL Proteome To Promote Increased Particle Uptake By Hepatocytes

• DOI: 10.1161/atvb.44.suppl_1.3043
• Publication Date: 2024-07-24T13:03:55Z
• Authors: Pheruza Tarapore; Debi Swertfeger; Jamie C Morris; Snigdha Sarkar; Yi He; John T Melchior; Min Liu; W. Sean Davidson
• Keywords: 0301 basic medicine; 03 medical and health sciences

The levels of circulating triglycerides (TG) carried in TG-rich lipoproteins (TGRL) and their remnants are causally associated with cardiovascular disease (CVD). Liberation of TG from lipoproteins to peripheral tissues is modulated by TGRL-associated proteins including apolipoproteln A5 (ApoA5), which has been reported to profoundly impact TG metabolism. Present at ~150 ng/ml in plasma, it has been thought to work via stimulation (or de-repression) of lipoprotein lipase (LPL), which hydrolyzes TG to deliver fatty acids to cells. To determine whether ApoA5 may alter the proteomic composition of VLDL, we examined the VLDL particle proteome from C57BL/6J WT and C57BL/6J apoA5 KO mice by mass spectrometry. ApoA5 presence was associated with increased VLDL apoE and apoM content and reduced levels of apoA1 and apoD, compared to VLDL from apoA5 KO mice. Presence of apoA5 also tracked with increased levels of the serine protease plasmin and decreased levels of its inhibitor alpha2-microglobulin on the VLDL. Immunoblotting analyses confirmed these results. Despite large differences in apoA5 content, VLDL from WT or KO mice behaved similarly as a substrate for recombinant human LPL in vitro . However, we observed that VLDL from apoA5 KO mice was internalized by cultured mouse hepatocytes less efficiently than WT VLDL (Kd 80±9.0 vs. 35±10 μg/ml). Notably, when recombinant mouse apoA5 was added back to apoA5 KO plasma, levels of VLDL apoE and apoM were rescued, and uptake efficiency was restored (Kd 29±8.0). Our current working model is that ApoA5 alters the proteome of TGRL in ways that affect remnant particle uptake by the liver, perhaps via apoE. ApoA5 may also affect plasmin levels/activity which was recently linked to LPL regulation.