Molecular Structures of Citrus Flavonoids Determine Their Effects on Lipid Metabolism in HepG2 Cells by Primarily Suppressing ApoB Secretion

• Published in: Journal of agricultural and food chemistry 2011-05, Vol.59 (9), p.4496-4503
• Main Authors: Lin, Yuguang, Vermeer, Mario A, Bos, Wil, van Buren, Leo, Schuurbiers, Eric, Miret-Catalan, Silvia, Trautwein, Elke A
• Format: Article
• Language: English
• Subjects: Apolipoproteins B - genetics; Apolipoproteins B - metabolism; Bioactive Constituents; Biological and medical sciences; blood; chemical structure; cholesterol; Citrus; Citrus - chemistry; Down-Regulation; enzyme-linked immunosorbent assay; flavonoids; Flavonoids - chemistry; Flavonoids - pharmacology; Food industries; Fruit and vegetable industries; Fundamental and applied biological sciences. Psychology; Hep G2 Cells; Humans; inhibitory concentration 50; lipid metabolism; Lipid Metabolism - drug effects; Liver - metabolism; mechanism of action; Molecular Structure; Plant Extracts - chemistry; Plant Extracts - pharmacology; secretion; Structure-Activity Relationship
• ISSN: 0021-8561; 1520-5118
• DOI: 10.1021/jf1044475

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 14C-acetate and 14C-glycerol, respectively, whereas apoB secretion was determined by ELISA. Results show that two polymethoxylated citrus flavonoids (PMFs), tangeretin and nobiletin, potently inhibited apoB secretion (IC50 = 13 and 29 μM, respectively) and modestly inhibited CH synthesis (IC50 = 49 and 68 μM) and TG synthesis (IC50 = 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 (IC50 > 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.