Structural determinants in ApoA-I amyloidogenic variants explain improved cholesterol metabolism despite low HDL levels

Biochim Biophys Acta Mol Basis Dis. 2017 Dec;1863(12):3038-3048. doi: 10.1016/j.bbadis.2017.09.001. Epub 2017 Sep 6.

Abstract

Twenty Apolipoprotein A-I (ApoA-I) variants are responsible for a systemic hereditary amyloidosis in which protein fibrils can accumulate in different organs, leading to their failure. Several ApoA-I amyloidogenic mutations are also associated with hypoalphalipoproteinemia, low ApoA-I and high-density lipoprotein (HDL)-cholesterol plasma levels; however, subjects affected by ApoA-I-related amyloidosis do not show a higher risk of cardiovascular diseases (CVD). The structural features, the lipid binding properties and the functionality of four ApoA-I amyloidogenic variants were therefore inspected in order to clarify the paradox observed in the clinical phenotype of the affected subjects. Our results show that ApoA-I amyloidogenic variants are characterized by a different oligomerization pattern and that the position of the mutation in the ApoA-I sequence affects the molecular structure of the formed HDL particles. Although lipidation increases ApoA-I proteins stability, all the amyloidogenic variants analyzed show a lower affinity for lipids, both in vitro and in ex vivo mouse serum. Interestingly, the lower efficiency at forming HDL particles is compensated by a higher efficiency at catalysing cholesterol efflux from macrophages. The decreased affinity of ApoA-I amyloidogenic variants for lipids, together with the increased efficiency in the cholesterol efflux process, could explain why, despite the unfavourable lipid profile, patients affected by ApoA-I related amyloidosis do not show a higher CVD risk.

Keywords: Amyloidosis; Apolipoprotein A-I; Cholesterol efflux; High-density lipoprotein; Hypoalphalipoproteinemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloidosis / metabolism
  • Animals
  • Apolipoprotein A-I / chemistry*
  • Apolipoprotein A-I / genetics
  • Apolipoprotein A-I / metabolism*
  • Binding Sites
  • Cholesterol / blood
  • Cholesterol / metabolism*
  • Cholesterol, HDL / metabolism*
  • Dyslipidemias / metabolism*
  • Humans
  • Hypoalphalipoproteinemias / metabolism
  • Lipid Metabolism
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Protein Structure, Secondary
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Sequence Analysis, Protein
  • Structure-Activity Relationship

Substances

  • Apolipoprotein A-I
  • Cholesterol, HDL
  • Recombinant Proteins
  • Cholesterol