期刊
EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY
卷 27, 期 15, 页码 1606-1616出版社
OXFORD UNIV PRESS
DOI: 10.1177/2047487319894114
关键词
Lipoprotein lipase; atherosclerosis; postprandial lipid metabolism; apolipoproteins; chylomicrons; HDL function; HDL metabolism; LCAT; lipoprotein metabolism; CETP
资金
- National Institute for Health and Medical Research (INSERM
- Paris, France)
- University of Pierre and Marie Curie (UPMC
- Paris, France)
- ICAN (Paris, France)
- China Scholarship Council (CSC, China)
- CAPES (Brazil)
- FAPESP (Brazil)
- CONICET (Buenos Aires, Argentina)
- University of Buenos Aires [UBACyT CB23]
- Craveri Foundation
- CONICET [PIP 516]
Background 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. Methods To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor (R) cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase. Results 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-3]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis. Conclusions 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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