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IMPACT OF HEPATIC APOLIPOPROTEIN A-IV EXPRESSION ON VLDL PARTICLE EXPANSION, TRIGLYCERIDE SECRETION, AND STEATOSIS

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abstract
Several apolipoproteins (apo) can impact triglyceride (TG) transport by modulating VLDL assembly and secretion. Here we explore the impact of apoA-IV on VLDL particle expansion. Previous studies demonstrated that apoA-IV expression promotes apoB lipoprotein-mediated TG secretion in transfected enterocytes and hepatoma cells. We therefore examined the impact of apoA-IV expression on VLDL particle dynamics in stably transfected McA-RH7777 hepatoma cells. Expression of apoA-IV caused an increase in TG secretion that was attributed to 10.1 nm increase in VLDL1 particle diameter. While these data suggest that apoA-IV can directly impact VLDL particle expansion, there is no current evidence indicating that apoA-IV can promote lipid transport by this or any other mechanisms, in vivo. To explore the role of apoA-IV in vivo, we assessed the impact of both apoA-IV deficiency and overexpression on hepatic VLDL-mediated lipid efflux in two different mouse models of hepatic steatosis. Hepatic steatosis induced by either a high fat diet or enhanced de novo lipogenesis, caused by transgenic overexpression of a constitutively active form of SREBP-1a (SREBP-1aTg), was associated with a robust induction (up to 43-fold) 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 (r2 = 0.8965). To examine whether induction of apoA-IV affected hepatic TG secretion, SREBP-1aTg mice were crossed with apoA-IV knock out mice (A4KO). With Triton blockade of peripheral lipolysis, SREBP-1aTg/A4KO mice demonstrated a 24% reduction in hepatic TG secretion rate, relative to SREBP-1aTg controls, but no change in apoB production. Negative stain electron microscopy revealed a 33% decrease in the abundance of secreted large VLDL particles with diameters ≥120 nm. Conversely, mice infected with a recombinant human apoA-IV adenovirus demonstrated a 38% increase in hepatic TG secretion rate and a 39% reduction in liver TG content relative to LacZ controls, associated with a 43% increase in large diameter VLDL particles and no change in apoB secretion. In conclusion, 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.
subject
apoa-iv
steatosis
vldl
contributor
VerHague, Melissa (author)
Shelness, Gregory S (committee chair)
Parks, Griffith D (committee member)
Parks, John S (committee member)
Dawson, Paul A (committee member)
St. Clair, Richard W (committee member)
date
2013-08-23T08:35:14Z (accessioned)
2015-08-23T08:30:10Z (available)
2013 (issued)
degree
Molecular Pathology (discipline)
embargo
2015-08-23 (terms)
identifier
http://hdl.handle.net/10339/39014 (uri)
language
en (iso)
publisher
Wake Forest University
title
IMPACT OF HEPATIC APOLIPOPROTEIN A-IV EXPRESSION ON VLDL PARTICLE EXPANSION, TRIGLYCERIDE SECRETION, AND STEATOSIS
type
Dissertation

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