Abstract 172: Prodomain of Furin Promotes Phospholipid Transfer Protein Proteasomal Degradation in Hepatocytes

PLTP is one of the major modulators of lipoprotein metabolism and atherosclerosis development, however, very little is known about the regulation of PLTP. The effect of hepatic profurin expression on PLTP processing and function is investigated. We utilized adenovirus overexpressing prodomain of furin (profurin) in mouse liver to evaluate PLTP activity, mass, and plasma lipid levels. We co-expressed PLTP and profurin in Huh7 cells and studied their interaction. We found profurin expression significantly reduced plasma lipids, plasma PLTP activity and mass in all tested mouse models, compared with controls. Moreover, the expression of profurin dramatically reduced liver PLTP activity and protein level. We further explore the mechanism using in vivo and ex vivo approaches. We found that profurin can interact with intracellular PLTP, and promote its ubiquitination and proteasomal degradation, resulting in less PLTP secretion from the hepatocytes. Furin does not cleave PLTP, instead it forms a complex with PLTP, likely through its prodomain. Our study reveals that hepatic PLTP protein is targeted for proteasomal degradation by profurin overexpression, which could be a novel post-translational mechanism underlying PLTP regulation.