title: Hesperetin upregulates ABCA1 expression and promotes cholesterol efflux from THP-1 macrophages.
abstract: ABCA1, a member of the ATP-binding cassette transporter family, regulates high-density lipoprotein (HDL) metabolism and cholesterol transport. Its expression is upregulated mainly by the activation of the liver X receptor (LXR). Since ABCA1 plays a pivotal role in cholesterol and HDL metabolism, identification of a compound capable of increasing its expression may be beneficial for the prevention and therapy of atherosclerosis. Firefly luciferase reporter assays were developed for human ABCA1 promoters and LXR enhancers, and an in-house phytochemical library was screened. It was found that a citrus flavonoid, hesperetin (1), increased ABCA1 promoter and LXR enhancer activities in THP-1 macrophages. It was also found that this flavonoid promoted PPAR-enhancing activity. In accordance with these findings, 1 increased mRNA and protein expression of ABCA1 and consequently upregulated ApoA-I-mediated cholesterol efflux. These results provide evidence that 1 promotes ApoA-I-mediated cholesterol efflux from macrophages by increasing ABCA1 expression through the activation of LXRα and PPARγ.
authors.affiliation: Gifu International Institute of Biotechnology, 1-1 Naka-Fudogaoka, Kakamigahara, Gifu 504-0838, Japan. aiio@giib.or.jp
authors.forename: Akio
authors.initials: A
authors.lastname: Iio
authors.forename: Kenji
authors.initials: K
authors.lastname: Ohguchi
authors.forename: Munekazu
authors.initials: M
authors.lastname: Iinuma
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nozawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ito
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D006569:Hesperidin / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008075:Lipoproteins, HDL / Q000502:physiology; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D012333:RNA, Messenger; D006569:Hesperidin; C013015:hesperetin