title: Lipid regulation of the ABCB1 and ABCG2 multidrug transporters.
abstract: This chapter deals with the interactions of two medically important multidrug ABC transporters (MDR-ABC), ABCB1 and ABCG2, with lipid molecules. Both ABCB1 and ABCG2 are capable of transporting a wide range of hydrophobic drugs and xenobiotics and are involved in cancer chemotherapy resistance. Therefore, the exploration of their mechanism of action has major therapeutic consequences. As discussed here in detail, both ABCB1 and ABCG2 are significantly affected by various lipid compounds especially those residing in their close proximity in the plasma membrane. ABCB1 is capable of transporting lipids and lipid derivatives, and thus may alter the general membrane composition by "flopping" membrane lipid constituents, while there is no such information regarding ABCG2. Still, both ABCB1 and ABCG2 show complex interactions with a variety of lipid molecules, and the transporters are significantly modulated by cholesterol and cholesterol derivatives at the posttranslational level. In this chapter, we explore the molecular details of the direct transporter-lipid interactions, the potential role of lipid-sensor domains within the proteins, as well as the application of experimental site-directed mutagenesis, detailed structural studies, and in silico modeling for examining these interactions. We also discuss the regulation of ABCB1 and ABCG2 expression at the transcriptional level, occurring through nuclear receptors involved in lipid sensing. The better understanding of lipid interactions with these medically important MDR-ABC transporters may significantly improve further drug development and clinical treatment options.
authors: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors: Csilla
authors: C
authors: Hegedüs
authors: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
authors: Ágnes
authors: Á
authors: Telbisz
authors: MTA-SE Molecular Biophysics Research Group of the Hungarian Academy of Sciences, Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
authors: Tamás
authors: T
authors: Hegedűs
authors: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary; MTA-SE Molecular Biophysics Research Group of the Hungarian Academy of Sciences, Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.
authors: Balázs
authors: B
authors: Sarkadi
authors: MTA-SE Molecular Biophysics Research Group of the Hungarian Academy of Sciences, Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary. Electronic address: laczka.csilla@ttk.mta.hu.
authors: Csilla
authors: C
authors: Özvegy-Laczka
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis* / Q000235:genetics; D001692:Biological Transport / Q000235:genetics; D002462:Cell Membrane / Q000502:physiology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000502:physiology; D008563:Membrane Lipids / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D008563:Membrane Lipids; D009363:Neoplasm Proteins; D018160:Receptors, Cytoplasmic and Nuclear
keywords: ABC multidrug transporter; Cholesterol; Membrane lipids; Nuclear receptors