Unknown

Dataset Information

0

Modified sites and functional consequences of 4-oxo-2-nonenal adducts in HDL that are elevated in familial hypercholesterolemia.


ABSTRACT: The lipid aldehyde 4-oxo-2-nonenal (ONE) is a highly reactive protein crosslinker derived from peroxidation of n-6 polyunsaturated fatty acids and generated together with 4-hydroxynonenal (HNE). Lipid peroxidation product-mediated crosslinking of proteins in high-density lipoprotein (HDL) causes HDL dysfunction and contributes to atherogenesis. Although HNE is relatively well-studied, the role of ONE in atherosclerosis and in modifying HDL is unknown. Here, we found that individuals with familial hypercholesterolemia (FH) had significantly higher ONE-ketoamide (lysine) adducts in HDL (54.6 ± 33.8 pmol/mg) than healthy controls (15.3 ± 5.6 pmol/mg). ONE crosslinked apolipoprotein A-I (apoA-I) on HDL at a concentration of > 3 mol ONE per 10 mol apoA-I (0.3 eq), which was 100-fold lower than HNE, but comparable to the potent protein crosslinker isolevuglandin. ONE-modified HDL partially inhibited HDL's ability to protect against lipopolysaccharide (LPS)-induced tumor necrosis factor ? (TNF?) and interleukin-1? (IL-1?) gene expression in murine macrophages. At 3 eq, ONE dramatically decreased apoA-I exchange from HDL, from ?46.5 to ?18.4% (p < 0.001). Surprisingly, ONE modification of HDL or apoA-I did not alter macrophage cholesterol efflux capacity. LC-MS/MS analysis revealed that Lys-12, Lys-23, Lys-96, and Lys-226 in apoA-I are modified by ONE ketoamide adducts. Compared with other dicarbonyl scavengers, pentylpyridoxamine (PPM) most efficaciously blocked ONE-induced protein crosslinking in HDL and also prevented HDL dysfunction in an in vitro model of inflammation. Our findings show that ONE-HDL adducts cause HDL dysfunction and are elevated in individuals with FH who have severe hypercholesterolemia.

SUBMITTER: May-Zhang LS 

PROVIDER: S-EPMC6916491 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

altmetric image

Publications

Modified sites and functional consequences of 4-oxo-2-nonenal adducts in HDL that are elevated in familial hypercholesterolemia.

May-Zhang Linda S LS   Yermalitsky Valery V   Melchior John T JT   Morris Jamie J   Tallman Keri A KA   Borja Mark S MS   Pleasent Tiffany T   Amarnath Venkataraman V   Song Wenliang W   Yancey Patricia G PG   Davidson W Sean WS   Linton MacRae F MF   Davies Sean S SS  

The Journal of biological chemistry 20191030 50


The lipid aldehyde 4-oxo-2-nonenal (ONE) is a highly reactive protein crosslinker derived from peroxidation of n-6 polyunsaturated fatty acids and generated together with 4-hydroxynonenal (HNE). Lipid peroxidation product-mediated crosslinking of proteins in high-density lipoprotein (HDL) causes HDL dysfunction and contributes to atherogenesis. Although HNE is relatively well-studied, the role of ONE in atherosclerosis and in modifying HDL is unknown. Here, we found that individuals with familia  ...[more]

Similar Datasets

| S-EPMC6579115 | biostudies-literature
| S-EPMC6788465 | biostudies-literature
| S-EPMC4109763 | biostudies-literature
2017-08-25 | PXD007149 | Pride
| S-EPMC9627852 | biostudies-literature
| S-EPMC6087521 | biostudies-literature
| S-EPMC9091303 | biostudies-literature
| S-EPMC7874460 | biostudies-literature
| S-EPMC10837708 | biostudies-literature
| S-EPMC8050012 | biostudies-literature