Abstract 152: Myeloid Cell ADAM17 Impairs Hepatic Triglyceride-Rich Lipoprotein Clearance in an LDL Receptor-Deficient Mouse Model of Prediabetes

ADAM17 (A Disintegrin-like And Metalloproteinase 17) is a transmembrane protease that cleaves its substrates at the cell surface. Cell type-specific substrates cleaved by ADAM17, such as TNFα, can function locally and systemically. When fed a diet enriched in saturated fat, sucrose, and added cholesterol (DDC), Ldlr -/- mice develop prediabetes characterized by elevated triglyceride-rich lipoproteins (TRLs), obesity, glucose intolerance and atherosclerosis. Our results demonstrate that when ADAM17 is deleted from hematopoietic cells, DDC-fed Adam17 H-/- Ldlr -/- bone marrow transplant chimeras (n=15-30) are less obese and more insulin sensitive than wildtype Ldlr -/- chimeras. Adam17 H-/- chimeras show decreased plasma cholesterol and triglycerides, primarily due to a reduction in plasma VLDL assayed by FPLC fractionation. Atherosclerotic lesions are significantly (p<0.05) decreased in the brachiocephalic artery, aortic sinus and the aorta. When ADAM17 is deleted from myeloid cells, DDC-fed Adam17 M-/- Ldlr -/- bone marrow transplant chimeras recapitulate the phenotypes of Adam17 H-/- mice, suggesting that the phenotypes are mediated by myeloid cells. Mechanistic studies indicate that the reduced plasma VLDL levels in ADAM17-deficient chimeras are not due to reduced VLDL production or reduced intestinal uptake of triglycerides. Furthermore, analysis of pre- and post-heparin plasma demonstrates that lipoprotein lipase activity is not increased in the ADAM17-/- chimeras. Instead, characterization of the TRLs by proteomics and differential ion mobility analysis revealed that ADAM17-deficient chimeras have reduced levels of 25-30 nm TRL remnant particles (e.g., p=0.027 for 25 nm particles; n=8-10) and reduced levels of APOC1, APOC2 and APOC3 per particle. Together, these results are consistent with the proposal that deletion of ADAM17 in myeloid cells results in increased hepatic clearance of TRLs and their remnants. Our work suggests that myeloid cells play important roles in regulating hepatic TRL remnant clearance and associated atherosclerosis in a model of prediabetes.