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.
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 humanLp(a). OBJECTIVE: To determine the effects of Lp(a) in human serum on ABCA1cholesterol 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 humanABCA1, 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 ABCA1cholesterol 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 ABCA1cholesterol efflux by Lp(a). Our findings suggest an atherogenic role for Lp(a) through its ability to inhibit CEC.
Authors: Anand Rohatgi; Amit Khera; Jarett D Berry; Edward G Givens; Colby R Ayers; Kyle E Wedin; Ian J Neeland; Ivan S Yuhanna; Daniel R Rader; James A de Lemos; Philip W Shaul Journal: N Engl J Med Date: 2014-11-18 Impact factor: 91.245
Authors: Amit V Khera; Marina Cuchel; Margarita de la Llera-Moya; Amrith Rodrigues; Megan F Burke; Kashif Jafri; Benjamin C French; Julie A Phillips; Megan L Mucksavage; Robert L Wilensky; Emile R Mohler; George H Rothblat; Daniel J Rader Journal: N Engl J Med Date: 2011-01-13 Impact factor: 91.245
Authors: Baohai Shao; Xiaoyun Fu; Thomas O McDonald; Pattie S Green; Koji Uchida; Kevin D O'Brien; John F Oram; Jay W Heinecke Journal: J Biol Chem Date: 2005-08-25 Impact factor: 5.157
Authors: Carolina Bagnato; Jaykumar Thumar; Viveka Mayya; Sun-Il Hwang; Henry Zebroski; Kevin P Claffey; Christian Haudenschild; Jimmy K Eng; Deborah H Lundgren; David K Han Journal: Mol Cell Proteomics Date: 2007-03-05 Impact factor: 5.911
Authors: Margarita de la Llera-Moya; Denise Drazul-Schrader; Bela F Asztalos; Marina Cuchel; Daniel J Rader; George H Rothblat Journal: Arterioscler Thromb Vasc Biol Date: 2010-01-14 Impact factor: 8.311
Authors: Mohamad Navab; Susan Y Hama; Srinu T Reddy; Carey J Ng; Brian J Van Lenten; Hillel Laks; Alan M Fogelman; Srinu T Ready Journal: Curr Opin Lipidol Date: 2002-08 Impact factor: 4.776
Authors: Majid Nikpay; Anuj Goel; Hong-Hee Won; Leanne M Hall; Christina Willenborg; Stavroula Kanoni; Danish Saleheen; Theodosios Kyriakou; Christopher P Nelson; Jemma C Hopewell; Thomas R Webb; Lingyao Zeng; Abbas Dehghan; Maris Alver; Sebastian M Armasu; Kirsi Auro; Andrew Bjonnes; Daniel I Chasman; Shufeng Chen; Ian Ford; Nora Franceschini; Christian Gieger; Christopher Grace; Stefan Gustafsson; Jie Huang; Shih-Jen Hwang; Yun Kyoung Kim; Marcus E Kleber; King Wai Lau; Xiangfeng Lu; Yingchang Lu; Leo-Pekka Lyytikäinen; Evelin Mihailov; Alanna C Morrison; Natalia Pervjakova; Liming Qu; Lynda M Rose; Elias Salfati; Richa Saxena; Markus Scholz; Albert V Smith; Emmi Tikkanen; Andre Uitterlinden; Xueli Yang; Weihua Zhang; Wei Zhao; Mariza de Andrade; Paul S de Vries; Natalie R van Zuydam; Sonia S Anand; Lars Bertram; Frank Beutner; George Dedoussis; Philippe Frossard; Dominique Gauguier; Alison H Goodall; Omri Gottesman; Marc Haber; Bok-Ghee Han; Jianfeng Huang; Shapour Jalilzadeh; Thorsten Kessler; Inke R König; Lars Lannfelt; Wolfgang Lieb; Lars Lind; Cecilia M Lindgren; Marja-Liisa Lokki; Patrik K Magnusson; Nadeem H Mallick; Narinder Mehra; Thomas Meitinger; Fazal-Ur-Rehman Memon; Andrew P Morris; Markku S Nieminen; Nancy L Pedersen; Annette Peters; Loukianos S Rallidis; Asif Rasheed; Maria Samuel; Svati H Shah; Juha Sinisalo; Kathleen E Stirrups; Stella Trompet; Laiyuan Wang; Khan S Zaman; Diego Ardissino; Eric Boerwinkle; Ingrid B Borecki; Erwin P Bottinger; Julie E Buring; John C Chambers; Rory Collins; L Adrienne Cupples; John Danesh; Ilja Demuth; Roberto Elosua; Stephen E Epstein; Tõnu Esko; Mary F Feitosa; Oscar H Franco; Maria Grazia Franzosi; Christopher B Granger; Dongfeng Gu; Vilmundur Gudnason; Alistair S Hall; Anders Hamsten; Tamara B Harris; Stanley L Hazen; Christian Hengstenberg; Albert Hofman; Erik Ingelsson; Carlos Iribarren; J Wouter Jukema; Pekka J Karhunen; Bong-Jo Kim; Jaspal S Kooner; Iftikhar J Kullo; Terho Lehtimäki; Ruth J F Loos; Olle Melander; Andres Metspalu; Winfried März; Colin N Palmer; Markus Perola; Thomas Quertermous; Daniel J Rader; Paul M Ridker; Samuli Ripatti; Robert Roberts; Veikko Salomaa; Dharambir K Sanghera; Stephen M Schwartz; Udo Seedorf; Alexandre F Stewart; David J Stott; Joachim Thiery; Pierre A Zalloua; Christopher J O'Donnell; Muredach P Reilly; Themistocles L Assimes; John R Thompson; Jeanette Erdmann; Robert Clarke; Hugh Watkins; Sekar Kathiresan; Ruth McPherson; Panos Deloukas; Heribert Schunkert; Nilesh J Samani; Martin Farrall Journal: Nat Genet Date: 2015-09-07 Impact factor: 38.330
Authors: Tomas Vaisar; Jennifer L Gordon; Jake Wimberger; Jay W Heinecke; Alan L Hinderliter; David R Rubinow; Susan S Girdler; Katya B Rubinow Journal: J Clin Lipidol Date: 2020-11-24 Impact factor: 4.766
Authors: Ross O'Hagan; Alex R Berg; Christin G Hong; Philip M Parel; Nehal N Mehta; Heather L Teague Journal: Front Immunol Date: 2022-08-26 Impact factor: 8.786
Authors: Trynke van der Boom; Congzhuo Jia; Joop D Lefrandt; Margery A Connelly; Thera P Links; Uwe J F Tietge; Robin P F Dullaart Journal: J Clin Endocrinol Metab Date: 2020-09-01 Impact factor: 5.958