Identification of the Flavonoid Luteolin as a Repressor of the Transcription Factor Hepatocyte Nuclear Factor 4α

Abstract

Background: Flavonoids are naturally occurring compounds that can regulate certain transcription factors. Results: We identified the flavonoid luteolin as a repressor of HNF4␣ and revealed that dietary luteolin improves high-fat diet-induced metabolic disorder in mice. Conclusion: HNF4␣ is a target of luteolin. Significance: Modulation of HNF4␣ activity through luteolin may be of therapeutic value in atherosclerotic disease.

The effect of artichoke on lipid profile: A review of possible mechanisms of action

“…Longterm clinical trials are decisive to confirm the beneficial effects of artichoke leaf extract administration upon cardiovascular outcomes. [88], [89], [90]]. Reduced HNF4α expression also decreases the synthesis of apoB, consequently decreasing VLDL and LDL levels [88].…”

The flavonoid derivative 4′-nitro-6-hydroxyflavone suppresses the activity of HNF4α and stimulates the degradation of HNF4α protein through the activation of AMPK

“…7) Using this luciferase assay system, we identified that flavonoids such as flavones (luteolin, apigenin, chrysin, acacetin, and nobiletin) and flavonols (fisetin, kaempferol, and galangin) suppress the promoter activity of the MTP gene and that luteolin is the most effective flavonoid among the above compounds for suppression. 6) We also demonstrated that luteolin greater than 10 μM is required to suppress HNF4α target gene expression. Considering the low bioavailability of flavonoids, it would be preferable to find flavonoid derivatives that act at lower concentrations.…”

“…On the contrary, we have previously demonstrated that luteolin functions as a repressor of HNF4α, and that luteolin treatment suppresses the expression of HNF4α target genes, including HNF4α. 6) Luteolin is able to form a complex with HNF4α, thereby leading to the suppression of HNF4α activity. 6) Currently, the reasons for this difference in results remain unclear.…”

“…6) Luteolin is able to form a complex with HNF4α, thereby leading to the suppression of HNF4α activity. 6) Currently, the reasons for this difference in results remain unclear. AMPK activation by AICAR treatment has been reported to accelerate the degradation of HNF4α protein and suppress the transcriptional activity of HNF4α.…”

“…To identify low molecular weight compounds that inhibit HNF4α activity, we previously conducted a luciferase reporter gene assay employing the promoter region of the MTP gene, 6) which is a regulatory target of HNF4α. 7) Using this luciferase assay system, we identified that flavonoids such as flavones (luteolin, apigenin, chrysin, acacetin, and nobiletin) and flavonols (fisetin, kaempferol, and galangin) suppress the promoter activity of the MTP gene and that luteolin is the most effective flavonoid among the above compounds for suppression.…”