title: ApoA-IV modulates the secretory trafficking of apoB and the size of triglyceride-rich lipoproteins.
abstract: Although the evidence linking apoA-IV expression and triglyceride (TG)-rich lipoprotein assembly and secretion is compelling, the intracellular mechanisms by which apoA-IV could modulate these processes remain poorly understood. We therefore examined the functional impact of apoA-IV expression on endogenous apoB, TG, and VLDL secretion in stably transfected McA-RH7777 rat hepatoma cells. Expression of apoA-IV modified with the endoplasmic reticulum (ER) retention signal KDEL (apoA-IV-KDEL) dramatically decreased both the rate and efficiency of endogenous apoB secretion, suggesting a presecretory interaction between apoA-IV-KDEL and apoB or apoB-containing lipoproteins. Expression of native apoA-IV using either a constitutive or tetracycline-inducible promoter delayed the initial rate of apoB secretion and reduced the final secretion efficiency by ∼40%. However, whereas apoA-IV-KDEL reduced TG secretion by 75%, expression of native apoA-IV caused a 20-35% increase in TG secretion, accompanied by a ∼55% increase in VLDL-associated apoB, an increase in the TG:phospholipid ratio of secreted d < 1.006 lipoproteins, and a 10.1 nm increase in peak VLDL(1) particle diameter. Native apoA-IV expression had a negligible impact on expression of the MTP gene. These data suggest that by interacting with apoB in the secretory pathway, apoA-IV alters the trafficking kinetics of apoB-containing TG-rich lipoproteins through cellular lipidation compartments, which in turn, enhances particle expansion and increases TG secretion.
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Weinberg
authors.forename: James W
authors.initials: JW
authors.lastname: Gallagher
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Fabritius
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Shelness
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism*; D001055:Apolipoproteins B / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003470:Culture Media / Q000378:metabolism; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D050356:Lipid Metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D051381:Rats; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D001054:Apolipoproteins A; D001055:Apolipoproteins B; D002352:Carrier Proteins; D003470:Culture Media; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C022205:apolipoprotein A-IV; C106092:microsomal triglyceride transfer protein; D013752:Tetracycline; D004318:Doxycycline