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

Arterioscler Thromb Vasc Biol. 2013 Nov;33(11):2501-8. doi: 10.1161/ATVBAHA.113.301948. Epub 2013 Sep 12.

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.

Keywords: VLDL; apolipoprotein B; metabolic syndrome; nonalcoholic fatty liver disease; triglyceride.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins A / genetics*
  • Apolipoproteins A / metabolism
  • Atherosclerosis / metabolism
  • Atherosclerosis / physiopathology
  • Disease Models, Animal
  • Fatty Liver / metabolism
  • Fatty Liver / physiopathology*
  • Female
  • Gene Expression / physiology
  • Lipid Metabolism / physiology*
  • Lipoproteins, VLDL / metabolism*
  • Liver / metabolism
  • Liver / physiology*
  • Male
  • Mice
  • Mice, Knockout
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Triglycerides / metabolism*

Substances

  • Apolipoproteins A
  • Lipoproteins, VLDL
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides
  • apolipoprotein A-IV