Apolipoprotein A-IV expression in mouse liver enhances triglyceride secretion and reduces hepatic lipid content by promoting very low density lipoprotein particle expansion

Abstract

OBJECTIVE-: Previous studies demonstrated that apolipoprotein A-IV (apoA-IV) promotes apoB lipoprotein-mediated triglyceride (TG) secretion in transfected enterocytes and hepatoma cells; however, evidence for a role in lipid transport in vivo is lacking. Using mouse models, we explored the role of apoA-IV in hepatic very low density lipoprotein-mediated lipid efflux under conditions that promote hepatic steatosis. APPROACH AND RESULTS-: Hepatic steatosis, induced by either high-fat diet or enhanced de novo lipogenesis caused by transgenic overexpression of SREBP-1a (SREBP-1a), was associated with up to a 43-fold induction of hepatic apoA-IV mRNA and protein levels. In both models, a positive linear correlation between hepatic TG content and apoA-IV mRNA abundance was observed (r=0.8965). To examine whether induction of apoA-IV affected hepatic TG secretion, SREBP-1a mice were crossed with Apoa4 knockout mice. With Triton blockade of peripheral lipolysis, SREBP-1a/Apoa4 knockout mice demonstrated a 24% reduction in hepatic TG secretion rate, relative to SREBP-1a controls, but no change in apoB production. Negative stain electron microscopy revealed a 33% decrease in the abundance of secreted very low density lipoprotein particles with diameters ≥120 nm. Conversely, mice infected with a recombinant human apoA-IV adenovirus demonstrated a 52% increase in the hepatic TG secretion rate, relative to controls, a 38% reduction in liver TG content, and a 43% increase in large diameter (≥120 nm) very low density lipoprotein particles, with no change in apoB secretion. CONCLUSIONS-: Hepatic steatosis in mice induces hepatic apoA-IV expression, which in turn promotes lipoprotein particle expansion and reduces hepatic lipid burden without increasing the number of secreted atherogenic apoB-containing lipoprotein particles. © 2013 American Heart Association, Inc.