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High-density lipoprotein or cyclodextrin extraction of cholesterol from aggregated LDL reduces foam cell formation.

ABSTRACT: Low-density lipoprotein (LDL) deposition, aggregation and retention in the endothelial sub-intima are critical initiating events during atherosclerosis. Macrophages digest aggregated LDL (agLDL) through a process called exophagy. High-density lipoprotein (HDL) plays an atheroprotective role, but studies attempting to exploit it therapeutically have been unsuccessful, highlighting gaps in our current understanding of HDL function. Here, we characterized the role of HDL during exophagy of agLDL. We find that atherosclerotic plaque macrophages contact agLDL and form an extracellular digestive compartment similar to that observed in vitro During macrophage catabolism of agLDL in vitro, levels of free cholesterol in the agLDL are increased. HDL can extract free cholesterol directly from this agLDL and inhibit macrophage foam cell formation. Cholesterol-balanced hydroxypropyl-?-cyclodextrin similarly reduced macrophage cholesterol uptake and foam cell formation. Finally, we show that HDL can directly extract free cholesterol, but not cholesterol esters, from agLDL in the absence of cells. Together, these results suggest that the actions of HDL can directly extract free cholesterol from agLDL during catabolism, and provide a new context in which to view the complex relationship between HDL and atherosclerosis.

SUBMITTER: Singh RK

PROVIDER: S-EPMC6918773 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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High-density lipoprotein or cyclodextrin extraction of cholesterol from aggregated LDL reduces foam cell formation.

Singh Rajesh K RK Lund Frederik W FW Haka Abigail S AS Maxfield Frederick R FR

Journal of cell science 20191202 23

Low-density lipoprotein (LDL) deposition, aggregation and retention in the endothelial sub-intima are critical initiating events during atherosclerosis. Macrophages digest aggregated LDL (agLDL) through a process called exophagy. High-density lipoprotein (HDL) plays an atheroprotective role, but studies attempting to exploit it therapeutically have been unsuccessful, highlighting gaps in our current understanding of HDL function. Here, we characterized the role of HDL during exophagy of agLDL. W ...[more]

PMID: 31719160

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Project description:Low-density lipoprotein cholesterol (LDL-C) is the traditional measure of risk attributable to LDL. Non-high-density lipoprotein cholesterol (NHDL-C), apolipoprotein B (apoB), and LDL particle number (LDL-P) are alternative measures of LDL-related risk. However, the clinical utility of these measures may only become apparent among individuals for whom levels are inconsistent (discordant) with LDL-C.LDL-C was measured directly, NHDL-C was calculated, apoB was measured with immunoassay, and LDL-P was measured with nuclear magnetic resonance spectroscopy among 27 533 healthy women (median follow-up 17.2 years; 1070 incident coronary events). Participants were grouped by median LDL-C (121 mg/dL) and each of NHDL-C, apoB, and LDL-P. Discordance was defined as LDL-C greater than or equal to the median and the alternative measure less than the median, or vice versa. Despite high LDL-C correlations with NHDL-C, apoB, and LDL-P (r=0.910, 0.785, and 0.692; all P<0.0001), prevalence of LDL-C discordance as defined by median cut points was 11.6%, 18.9%, and 24.3% for NHDL-C, apoB, and LDL-P, respectively. Among women with LDL-C less than the median, coronary risk was underestimated for women with discordant (greater than or equal to the median) NHDL-C (age-adjusted hazard ratio, 2.92; 95% confidence interval, 2.33-3.67), apoB (2.48, 2.01-3.07), or LDL-P (2.32, 1.88-2.85) compared with women with concordant levels. Conversely, among women with LDL-C greater than or equal to the median, risk was overestimated for women with discordant (less than the median) NHDL-C (0.40, 0.29-0.57), apoB (0.34, 0.26-0.46), or LDL-P (0.42, 0.33-0.53). After multivariable adjustment for potentially mediating factors, including HDL cholesterol and triglycerides, coronary risk remained underestimated or overestimated by ?20% to 50% for women with discordant levels.For women with discordant LDL-related measures, coronary risk may be underestimated or overestimated when LDL-C alone is used.http://www.clinicaltrials.gov. Unique identifier: NCT00000479.

Project description:OBJECTIVE:The role of high-density lipoprotein (HDL) function in HIV-related atherosclerotic cardiovascular disease (CVD) is unclear. HDLs isolated from HIV [HIV(+)HDL] and HIV-uninfected individuals [HIV(-)HDL] were assessed for HDL function and ability to promote monocyte-derived foam cell formation (MDFCF; a key event in HIV-related CVD) ex vivo. DESIGN/METHODS:Using an established in-vitro model of atherogenesis and plasma samples from an established cross-sectional study of virologically suppressed HIV men on stable effective antiretroviral therapy and with low CVD risk (median age: 42 years; n?=?10), we explored the impact of native HDL [HIV(+)HDL] on MDFCF. In this exploratory study, we selected HIV(+)HDL known to be dysfunctional based on two independent measures of impaired HDL function: antioxidant (high HDLox) ability of HDL to release apolipoprotein A-I (ApoA-I) (low HDL-ApoA-I exchange). Five healthy men matched by age and race to the HIV group were included. Given that oxidation of HDL leads to abnormal HDL function, we also compared proatherogenic effects of HIV(+)HDL vs. chemically derived HDLox. The ex-vivo atherogenesis assay was performed using lipoproteins (purchased or isolated from plasma using ultracentrifugation) and monocytes purified via negative selection from healthy donors. RESULTS:HIV(+)HDL known to have reduced antioxidant function and rate of HDL/ApoAI exchange promoted MDFCF to a greater extent than HDL (33.0 vs. 26.2% foam cells; P?=?0.015). HDL oxidized in vitro also enhanced foam cell formation as compared with nonoxidized HDL (P?<?0.01). CONCLUSION:Dysfunctional HDL in virologically suppressed HIV individuals may potentiate atherosclerosis in HIV infection by promoting MDFCF.The role of HDL function in HIV-related atherosclerotic CVD is unclear. HDL isolated from HIV [HIV(+)HDL] and HIV-uninfected individuals [HIV(-)HDL] were assessed for HDL function and ability to promote foam cell formation ex vivo. HIV(+)HDL known to have reduced antioxidant function and rate of HDL/ApoA1 exchange promoted MDFCF to a greater extent than HDL(-)HDL (33.0 vs. 26.2% foam cells.Subject codes: Inflammation, Lipids and Cholesterol, Vascular Biology, Oxidant Stress, Atherosclerosis.

Dataset Information

High-density lipoprotein or cyclodextrin extraction of cholesterol from aggregated LDL reduces foam cell formation.

Publications

High-density lipoprotein or cyclodextrin extraction of cholesterol from aggregated LDL reduces foam cell formation.

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