title: Molecular structures of citrus flavonoids determine their effects on lipid metabolism in HepG2 cells by primarily suppressing apoB secretion.
abstract: This study investigated the underlying mechanisms of action for blood lipid lowering effects of citrus flavonoids and their methoxylated analogues (n = 19; dose range: 0-100 μM) in HepG2 cells. Cholesterol (CH) and triglyceride (TG) syntheses were assessed by measuring the incorporation of (14)C-acetate and (14)C-glycerol, respectively, whereas apoB secretion was determined by ELISA. Results show that two polymethoxylated citrus flavonoids (PMFs), tangeretin and nobiletin, potently inhibited apoB secretion (IC(50) = 13 and 29 μM, respectively) and modestly inhibited CH synthesis (IC(50) = 49 and 68 μM) and TG synthesis (IC(50) = 14 and 73 μM), without effecting LDL-receptor activity. Other PMFs (e.g., sinensetin) and non-PMFs (e.g., hesperetin and naringenin) had only weak effects on CH and TG syntheses and apoB secretion (IC(50) > 100 μM). The structure-activity analysis indicated that a fully methoxylated A-ring of the flavonoid structure was associated with a potent inhibitory activity on hepatic apoB secretion. In conclusion, this study using HepG2 cells indicates that citrus flavonoids with a fully methoxylated A-ring may lower blood CH and TG concentrations primarily by suppressing hepatic apoB secretion as a main underlying mode of action.
authors.affiliation: Unilever R&D Vlaardingen, Vlaardingen, The Netherlands. Yuguang.Lin@unilever.com
authors.forename: Yuguang
authors.initials: Y
authors.lastname: Lin
authors.forename: Mario A
authors.initials: MA
authors.lastname: Vermeer
authors.forename: Wil
authors.initials: W
authors.lastname: Bos
authors.forename: Leo
authors.initials: L
authors.lastname: van Buren
authors.forename: Eric
authors.initials: E
authors.lastname: Schuurbiers
authors.forename: Silvia
authors.initials: S
authors.lastname: Miret-Catalan
authors.forename: Elke A
authors.initials: EA
authors.lastname: Trautwein
mesh_terms: D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D002957:Citrus / Q000737:chemistry*; D015536:Down-Regulation; D005419:Flavonoids / Q000737:chemistry* / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000378:metabolism; D015394:Molecular Structure; D010936:Plant Extracts / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001055:Apolipoproteins B; D005419:Flavonoids; D010936:Plant Extracts