Apolipoprotein A-IV Expression in Mouse Liver Enhances Triglyceride Secretion and Reduces Hepatic Lipid Content by Promoting Very Low Density Lipoprotein Particle Expansion

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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 Tg ), 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 2 =0.8965). To examine whether induction of apoA-IV affected hepatic TG secretion, SREBP-1a Tg mice were crossed with Apoa4 knockout mice. With Triton blockade of peripheral lipolysis, SREBP-1a Tg / Apoa4 knockout mice demonstrated a 24% reduction in hepatic TG secretion rate, relative to SREBP-1a Tg 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.

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