TY - JOUR
T1 - Elevated Lipoprotein(a) Levels Lower ABCA1 Cholesterol Efflux Capacity
AU - Tavori, Hagai
AU - Fenton, Alexandra M.
AU - Plubell, Deanna L.
AU - Rosario, Sara
AU - Yerkes, Elisabeth
AU - Gasik, Rayna
AU - Miles, Joshua
AU - Bergstrom, Paige
AU - Minnier, Jessica
AU - Fazio, Sergio
AU - Pamir, Nathalie
N1 - Publisher Copyright:
© 2019 Endocrine Society.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Context: Elevated serum lipoprotein(a) [Lp(a)] levels are associated with increased cardiovascular disease risk. ABCA1-mediated cholesterol efflux from macrophages may be an antiatherogenic process. Plasminogen (PLG) is a driver of ABCA1-mediated cholesterol efflux, and its action is inhibited by purified human Lp(a). Objective: To determine the effects of Lp(a) in human serum on ABCA1 cholesterol efflux. Methods: Cholesterol efflux capacity (CEC) was measured with two different cell-culture models using serum from 76 patients with either low (<50 mg/dL) or high (>50 mg/dL) Lp(a) levels. Results: Using cAMP-stimulated J774 macrophages or baby hamster kidney fibroblasts overexpressing human ABCA1, we show that CEC was lower in patients with high Lp(a) levels compared with patients with low levels (-30.6%, P = 0.002 vs-24.1%, P < 0.001, respectively). Total-serum CEC negatively correlated with Lp(a) levels (r =-0.433, P = 0.0007 vs r =-0.505, P = 0.0011, respectively). These negative associations persisted after adjusting for serum cholesterol, age, sex, and statin use in a multiple linear regression model (adjusted R2 = 0.413 or 0.405, respectively) and were strengthened when further adjusting for the interaction between Lp(a) and PLG levels (adjusted R2 = 0.465 and 0.409, respectively). Total-serum and isolated Lp(a) from patients with high Lp(a) inhibited PLG-mediated ABCA1 cholesterol efflux. Conclusion: Total-serum CEC is reduced in patients with high Lp(a) levels. This is in part due to the inhibition of PLG-mediated ABCA1 cholesterol efflux by Lp(a). Our findings suggest an atherogenic role for Lp(a) through its ability to inhibit CEC.
AB - Context: Elevated serum lipoprotein(a) [Lp(a)] levels are associated with increased cardiovascular disease risk. ABCA1-mediated cholesterol efflux from macrophages may be an antiatherogenic process. Plasminogen (PLG) is a driver of ABCA1-mediated cholesterol efflux, and its action is inhibited by purified human Lp(a). Objective: To determine the effects of Lp(a) in human serum on ABCA1 cholesterol efflux. Methods: Cholesterol efflux capacity (CEC) was measured with two different cell-culture models using serum from 76 patients with either low (<50 mg/dL) or high (>50 mg/dL) Lp(a) levels. Results: Using cAMP-stimulated J774 macrophages or baby hamster kidney fibroblasts overexpressing human ABCA1, we show that CEC was lower in patients with high Lp(a) levels compared with patients with low levels (-30.6%, P = 0.002 vs-24.1%, P < 0.001, respectively). Total-serum CEC negatively correlated with Lp(a) levels (r =-0.433, P = 0.0007 vs r =-0.505, P = 0.0011, respectively). These negative associations persisted after adjusting for serum cholesterol, age, sex, and statin use in a multiple linear regression model (adjusted R2 = 0.413 or 0.405, respectively) and were strengthened when further adjusting for the interaction between Lp(a) and PLG levels (adjusted R2 = 0.465 and 0.409, respectively). Total-serum and isolated Lp(a) from patients with high Lp(a) inhibited PLG-mediated ABCA1 cholesterol efflux. Conclusion: Total-serum CEC is reduced in patients with high Lp(a) levels. This is in part due to the inhibition of PLG-mediated ABCA1 cholesterol efflux by Lp(a). Our findings suggest an atherogenic role for Lp(a) through its ability to inhibit CEC.
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U2 - 10.1210/jc.2018-02708
DO - 10.1210/jc.2018-02708
M3 - Article
C2 - 31220285
AN - SCOPUS:85071994717
SN - 0021-972X
VL - 104
SP - 4793
EP - 4803
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 10
ER -