title: 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.
  
  
  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.
authors.affiliation: From the Department of Pathology (M.A.V., D.C., G.S.S.), Department of Internal Medicine (R.B.W.), and Department of Physiology & Pharmacology (R.B.W.), Wake Forest School of Medicine, Winston-Salem, NC.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: VerHague
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.forename: Richard B
authors.initials: RB
authors.lastname: Weinberg
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Shelness
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D050356:Lipid Metabolism / Q000502:physiology*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001054:Apolipoproteins A; D008079:Lipoproteins, VLDL; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C022205:apolipoprotein A-IV
keywords: VLDL; apolipoprotein B; metabolic syndrome; nonalcoholic fatty liver disease; triglyceride