title: Enhanced binding of apolipoprotein A-I variants associated with hypertriglyceridemia to triglyceride-rich particles.
abstract: Hypertriglyceridemia (HTG) is a common lipid abnormality in humans. However, its etiology remains largely unknown. It was shown that severe HTG can be induced in mice by overexpression of wild-type (WT) apolipoprotein E (apoE) or specific apoA-I mutants. Certain mutations in apoE4 were found to affect plasma triglyceride (TG) levels in mice overexpressing the protein. HTG appeared to positively correlate with the ability of the apoE4 variants to bind to TG-rich particles, protein destabilization, and the exposure of protein hydrophobic surface in solution. Here, we propose that the apoA-I mutations that cause HTG may also lead to changes in the conformation and stability that promote binding of apoA-I to TG-rich lipoproteins. To test this hypothesis, we studied binding to TG-rich emulsion and biophysical properties of the apoA-I mutants that induce HTG, apoA-I[E110A/E111A] and apoA-I[Δ(61-78)], and compared them to those of WT apoA-I and another apoA-I mutant, apoA-I[Δ(89-99)], that does not induce HTG but causes hypercholesterolemia in mice. We found that the apoA-I[E110A/E111A] and apoA-I[Δ(61-78)] mutations lead to enhanced binding of apoA-I to TG-rich particles, destabilization, and greater exposure of the hydrophobic surface of the protein. The apoA-I[Δ(89-99)] mutant did not show enhanced binding to the emulsion or a more exposed hydrophobic surface. Thus, like apoE4, the apoA-I variants that cause HTG in mice have the altered conformation and stability that facilitate their binding to TG-rich lipoproteins and thereby may lead to the reduced level of lipolysis of these lipoproteins. While many factors may be involved in induction of HTG, we suggest that an increased level of association of destabilized loosely folded apolipoproteins with TG-rich lipoproteins may contribute to some cases of HTG in humans.
authors.affiliation: Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, Massachusetts 02118, United States. igorshko@bu.edu
authors.forename: Irina N
authors.initials: IN
authors.lastname: Gorshkova
authors.forename: David
authors.initials: D
authors.lastname: Atkinson
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004655:Emulsions; D015228:Hypertriglyceridemia / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D055550:Protein Stability; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D016632:Apolipoprotein A-I; D004655:Emulsions; D050505:Mutant Proteins; D014280:Triglycerides