Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease

Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease....

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Published in:European journal of preventive cardiology Vol. 27; no. 15; p. 1606
Main Authors: Feng, Ma, Darabi, Maryam, Tubeuf, Emilie, Canicio, Aurélie, Lhomme, Marie, Frisdal, Eric, Lanfranchi-Lebreton, Sandrine, Matheron, Lucrèce, Rached, Fabiana, Ponnaiah, Maharajah, Serrano, Jr, Carlos V, Santos, Raul D, Brites, Fernando, Bolbach, Gerard, Gautier, Emmanuel, Huby, Thierry, Carrie, Alain, Bruckert, Eric, Guerin, Maryse, Couvert, Philippe, Giral, Philippe, Lesnik, Philippe, Le Goff, Wilfried, Guillas, Isabelle, Kontush, Anatol
Format: Journal Article
Language:English
Published: England 01.10.2020
Subjects:
atherosclerosis
CETP
apolipoproteins
lipoprotein metabolism
HDL function
LCAT
Lipoprotein lipase
HDL metabolism
chylomicrons
postprandial lipid metabolism
ISSN:2047-4881, 2047-4881
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Summary:Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk. To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase. When the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (-45%) and type 2 diabetes (-25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (-20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [ H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis. Free cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.
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ISSN:2047-4881
2047-4881
DOI:10.1177/2047487319894114