A novel approach to oral apoA-I mimetic therapy

J Lipid Res. 2013 Apr;54(4):995-1010. doi: 10.1194/jlr.M033555. Epub 2013 Feb 2.

Abstract

Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide, 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to Western diet (WD) at 2.2% by weight, and fed to LDL receptor-null (LDLR(-/-)) mice at 45 mg/kg/day 6F. After 13 weeks, the percent of the aorta with lesions was 4.1 ± 4%, 3.3 ± 2.4%, and 1.9 ± 1.4% for WD, WD + EV, and WD + 6F, respectively (WD + 6F vs. WD, P = 0.0134; WD + 6F vs. WD + EV, P = 0.0386; WD + EV vs. WD, not significant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD + 6F mice; P < 0.0295. HDL cholesterol and paroxonase-1 activity (PON) were higher in WD + 6F mice (P = 0.0055 and P = 0.0254, respectively), but not in WD + EV mice. Plasma SAA, total cholesterol, triglycerides, LPA, and 15-hydroxyeicosatetraenoic acid (HETE) levels positively correlated with lesions (P < 0.0001); HDL cholesterol and PON were inversely correlated (P < 0.0001). After feeding WD + 6F: i) intact 6F was detected in small intestine (but not in plasma); ii) small intestine LPA was decreased compared with WD + EV (P < 0.0469); and iii) small intestine LPA 18:2 positively correlated with the percent of the aorta with lesions (P < 0.0179). These data suggest that 6F acts in the small intestine and provides a novel approach to oral apoA-I mimetic therapy.

Publication types

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

MeSH terms

  • Animals
  • Apolipoprotein A-I / chemistry*
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / drug therapy
  • Cholesterol / blood
  • Female
  • Hydroxyeicosatetraenoic Acids / blood
  • Intestine, Small / metabolism
  • Lycopersicon esculentum / genetics
  • Lycopersicon esculentum / metabolism
  • Lysophospholipids / blood
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptides / chemistry*
  • Peptides / genetics
  • Peptides / metabolism
  • Peptides / therapeutic use*
  • Plants, Genetically Modified / genetics
  • Plants, Genetically Modified / metabolism
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Triglycerides / blood

Substances

  • Apolipoprotein A-I
  • Apolipoproteins E
  • Hydroxyeicosatetraenoic Acids
  • Lysophospholipids
  • Peptides
  • Receptors, LDL
  • Triglycerides
  • Cholesterol
  • lysophosphatidic acid