1 research outputs found
Structure–function analysis of naturally occurring apolipoprotein A-I L144R, A164S and L178P mutants provides insight on their role on HDL levels and cardiovascular risk
Naturally occurring point mutations in apolipoprotein A-I (apoA-I), the major protein component of high-density lipoprotein
(HDL), may afect plasma HDL-cholesterol levels and cardiovascular risk. Here, we evaluated the efect of human apoA-I
mutations L144R (associated with low HDL-cholesterol), L178P (associated with low HDL-cholesterol and increased cardiovascular risk) and A164S (associated with increased cardiovascular risk and mortality without low HDL-cholesterol) on
the structural integrity and functions of lipid-free and lipoprotein-associated apoA-I in an efort to explain the phenotypes of
subjects carrying these mutations. All three mutants, in lipid-free form, presented structural and thermodynamic aberrations,
with apoA-I[L178P] presenting the greatest thermodynamic destabilization. Additionally, apoA-I[L178P] displayed reduced
ABCA1-mediated cholesterol elux capacity. When in reconstituted HDL (rHDL), apoA-I[L144R] and apoA-I[L178P] were
more thermodynamically destabilized compared to wild-type apoA-I, both displayed reduced SR-BI-mediated cholesterol
elux capacity and apoA-I[L144R] showed severe LCAT activation defect. ApoA-I[A164S] was thermodynamically unaffected when in rHDL, but exhibited a series of functional defects. Speciically, it had reduced ABCG1-mediated cholesterol
and 7-ketocholesterol elux capacity, failed to reduce ROS formation in endothelial cells and had reduced capacity to induce
endothelial cell migration. Mechanistically, the latter was due to decreased capacity of rHDL-apoA-I[A164S] to activate Akt
kinase possibly by interacting with endothelial LOX-1 receptor. The impaired capacity of rHDL-apoA-I[A164S] to preserve
endothelial function may be related to the increased cardiovascular risk for this mutation. Overall, our structure–function
analysis of L144R, A164S and L178P apoA-I mutants provides insights on how HDL-cholesterol levels and/or atheroprotective properties of apoA-I/HDL are impaired in carriers of these mutations