Bilirubin Decreases Macrophage Cholesterol Efflux and ATP‐Binding Cassette Transporter A1 Protein Expression
BackgroundMild but chronically elevated circulating unconjugated bilirubin is associated with reduced total and low‐density lipoprotein cholesterol concentration, which is associated with reduced cardiovascular disease risk. We aimed to investigate whether unconjugated bilirubin influences macrophag...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2017-05-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.117.005520 |
| _version_ | 1819178457229164544 |
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| author | Dongdong Wang Anela Tosevska Elke H. Heiß Angela Ladurner Christine Mölzer Marlies Wallner Andrew Bulmer Karl‐Heinz Wagner Verena M. Dirsch Atanas G. Atanasov |
| author_facet | Dongdong Wang Anela Tosevska Elke H. Heiß Angela Ladurner Christine Mölzer Marlies Wallner Andrew Bulmer Karl‐Heinz Wagner Verena M. Dirsch Atanas G. Atanasov |
| author_sort | Dongdong Wang |
| collection | DOAJ |
| description | BackgroundMild but chronically elevated circulating unconjugated bilirubin is associated with reduced total and low‐density lipoprotein cholesterol concentration, which is associated with reduced cardiovascular disease risk. We aimed to investigate whether unconjugated bilirubin influences macrophage cholesterol efflux, as a potential mechanism for the altered circulating lipoprotein concentrations observed in hyperbilirubinemic individuals. Methods and ResultsCholesterol efflux from THP‐1 macrophages was assessed using plasma obtained from normo‐ and hyperbilirubinemic (Gilbert syndrome) humans (n=60 per group) or (heterozygote/homozygote Gunn) rats (n=20 per group) as an acceptor. Hyperbilirubinemic plasma from patients with Gilbert syndrome and Gunn rats induced significantly reduced cholesterol efflux compared with normobilirubinemic plasma. Unconjugated bilirubin (3–17.1 μmol/L) exogenously added to plasma‐ or apolipoprotein A1–supplemented media also decreased macrophage cholesterol efflux in a concentration‐ and time‐dependent manner. We also showed reduced protein expression of the ATP‐binding cassette transporter A1 (ABCA1), a transmembrane cholesterol transporter involved in apolipoprotein A1–mediated cholesterol efflux, in THP‐1 macrophages treated with unconjugated bilirubin and in peripheral blood mononuclear cells obtained from hyperbilirubinemic individuals. Furthermore, we demonstrated that bilirubin accelerates the degradation rate of the ABCA1 protein in THP‐1 macrophages. ConclusionsCholesterol efflux from THP‐1 macrophages is decreased in the presence of plasma obtained from humans and rats with mild hyperbilirubinemia. A direct effect of unconjugated bilirubin on cholesterol efflux was demonstrated and is associated with decreased ABCA1 protein expression. These data improve our knowledge concerning bilirubin's impact on cholesterol transport and represent an important advancement in our understanding of bilirubin's role in cardiovascular disease. |
| first_indexed | 2024-12-22T21:42:51Z |
| format | Article |
| id | doaj.art-8880937604a84a2a8e2de4986d7f46dd |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-22T21:42:51Z |
| publishDate | 2017-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-8880937604a84a2a8e2de4986d7f46dd2022-12-21T18:11:34ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802017-05-016510.1161/JAHA.117.005520Bilirubin Decreases Macrophage Cholesterol Efflux and ATP‐Binding Cassette Transporter A1 Protein ExpressionDongdong Wang0Anela Tosevska1Elke H. Heiß2Angela Ladurner3Christine Mölzer4Marlies Wallner5Andrew Bulmer6Karl‐Heinz Wagner7Verena M. Dirsch8Atanas G. Atanasov9Department of Pharmacognosy, University of Vienna, AustriaResearch Platform Active Ageing, University of Vienna, AustriaDepartment of Pharmacognosy, University of Vienna, AustriaDepartment of Pharmacognosy, University of Vienna, AustriaDepartment of Nutritional Sciences, University of Vienna, AustriaDepartment of Nutritional Sciences, University of Vienna, AustriaSchool of Medical Science and Menzies Health Institute Queensland, Gold Coast, AustraliaResearch Platform Active Ageing, University of Vienna, AustriaDepartment of Pharmacognosy, University of Vienna, AustriaDepartment of Pharmacognosy, University of Vienna, AustriaBackgroundMild but chronically elevated circulating unconjugated bilirubin is associated with reduced total and low‐density lipoprotein cholesterol concentration, which is associated with reduced cardiovascular disease risk. We aimed to investigate whether unconjugated bilirubin influences macrophage cholesterol efflux, as a potential mechanism for the altered circulating lipoprotein concentrations observed in hyperbilirubinemic individuals. Methods and ResultsCholesterol efflux from THP‐1 macrophages was assessed using plasma obtained from normo‐ and hyperbilirubinemic (Gilbert syndrome) humans (n=60 per group) or (heterozygote/homozygote Gunn) rats (n=20 per group) as an acceptor. Hyperbilirubinemic plasma from patients with Gilbert syndrome and Gunn rats induced significantly reduced cholesterol efflux compared with normobilirubinemic plasma. Unconjugated bilirubin (3–17.1 μmol/L) exogenously added to plasma‐ or apolipoprotein A1–supplemented media also decreased macrophage cholesterol efflux in a concentration‐ and time‐dependent manner. We also showed reduced protein expression of the ATP‐binding cassette transporter A1 (ABCA1), a transmembrane cholesterol transporter involved in apolipoprotein A1–mediated cholesterol efflux, in THP‐1 macrophages treated with unconjugated bilirubin and in peripheral blood mononuclear cells obtained from hyperbilirubinemic individuals. Furthermore, we demonstrated that bilirubin accelerates the degradation rate of the ABCA1 protein in THP‐1 macrophages. ConclusionsCholesterol efflux from THP‐1 macrophages is decreased in the presence of plasma obtained from humans and rats with mild hyperbilirubinemia. A direct effect of unconjugated bilirubin on cholesterol efflux was demonstrated and is associated with decreased ABCA1 protein expression. These data improve our knowledge concerning bilirubin's impact on cholesterol transport and represent an important advancement in our understanding of bilirubin's role in cardiovascular disease.https://www.ahajournals.org/doi/10.1161/JAHA.117.005520ATP‐binding cassette transporterbilirubincardiovascular diseasecholesterolcholesterol homeostasis |
| spellingShingle | Dongdong Wang Anela Tosevska Elke H. Heiß Angela Ladurner Christine Mölzer Marlies Wallner Andrew Bulmer Karl‐Heinz Wagner Verena M. Dirsch Atanas G. Atanasov Bilirubin Decreases Macrophage Cholesterol Efflux and ATP‐Binding Cassette Transporter A1 Protein Expression Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease ATP‐binding cassette transporter bilirubin cardiovascular disease cholesterol cholesterol homeostasis |
| title | Bilirubin Decreases Macrophage Cholesterol Efflux and ATP‐Binding Cassette Transporter A1 Protein Expression |
| title_full | Bilirubin Decreases Macrophage Cholesterol Efflux and ATP‐Binding Cassette Transporter A1 Protein Expression |
| title_fullStr | Bilirubin Decreases Macrophage Cholesterol Efflux and ATP‐Binding Cassette Transporter A1 Protein Expression |
| title_full_unstemmed | Bilirubin Decreases Macrophage Cholesterol Efflux and ATP‐Binding Cassette Transporter A1 Protein Expression |
| title_short | Bilirubin Decreases Macrophage Cholesterol Efflux and ATP‐Binding Cassette Transporter A1 Protein Expression |
| title_sort | bilirubin decreases macrophage cholesterol efflux and atp binding cassette transporter a1 protein expression |
| topic | ATP‐binding cassette transporter bilirubin cardiovascular disease cholesterol cholesterol homeostasis |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.117.005520 |
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