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Structure dynamics of ApoA-I amyloidogenic variants in small HDL increase their ability to mediate cholesterol efflux

ABSTRACT: Specific mutations in Apolipoprotein A-I (ApoA-I) of high-density lipoprotein (HDL) are responsible for a late-onset systemic amyloidosis. Carriers do not exhibit increased cardiovascular disease risk despite reduced levels of ApoA-I/ HDL-cholesterol. To explain this paradox, we show that the HDL particle profile of L75P and L174S patients presents a higher relative abundance of the 8.4 nm vs 9.6 nm particles, and that serum from patients, as well as reconstituted 8.4 and 9.6 nm HDL particles (rHDL), possess increased capacity to catalyze cholesterol efflux from macrophages. Synchrotron radiation circular dichroism and hydrogen-deuterium exchange revealed that the variants in 8.4 nm rHDL have altered secondary structure composition and display a more flexible binding to lipids compared to their native counterpart. The reduced HDL-cholesterol levels of patients carrying ApoA-I amyloidogenic variants are thus balanced by higher proportion of small, dense HDL particles and better cholesterol efflux due to altered, region-specific protein structure dynamics.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Cardiovascular System Disease

SUBMITTER: Simon Ekström

LAB HEAD: Jens O. Lagerstedt

PROVIDER: PXD021266 | Pride | 2020-11-20

REPOSITORIES: Pride

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			Action	DRS
	20_07_24.hdx	Other
	Apo_Lipid_Free_0.raw	Raw
	Apo_Lipid_Free_151354_30.raw	Raw
	Apo_Lipid_Free_160932_300.raw	Raw
	Apo_Lipid_Free_180853_9000.raw	Raw

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Aortic gene expression profiles show how APOA-I levels modulate infammation, lysosomal activity and sphingolipid metabolism in murine atherosclerosis

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