The Citrus Flavonoids Hesperetin and Nobiletin Differentially Regulate Low Density Lipoprotein Receptor Gene Transcription in HepG2 Liver Cells  

Oleh:

Morin, Brian ; Nichols, LaNita A. ; Zalasky, Katherine M. ; Davis, J. Wade ; Manthey, John A. ; Holland, Lene J.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: JN: The Journal of Nutrition vol. 138 no. 07 (Jul. 2008), page 1274.

Ketersediaan

Perpustakaan FK Nomor Panggil: J42.K.2008.01 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Isi artikel

Reduction of plasma cholesterol by citrus flavonoids is associated with effects on specific liver functions related to lipid handling. In previous in vivo studies, polymethoxylated flavones (PMF) reduced plasma cholesterol levels at lower doses than required for flavanones. To delineate hepatic mechanisms that underlie this differential potency, we used HepG2 cells to quantitate effects on expression of the LDL receptor (LDLR) gene. A dose-response analysis showed that 200 µmol/L hesperetin, a flavanone present as a disaccharide in oranges, increased LDLR mRNA levels 3.6- to 4.7-fold of the untreated control. In contrast, nobiletin, a PMF found at the highest concentration in oranges and tangerines, achieved maximal stimulation of 1.5- to 1.6-fold of control at only 5 µmol/L. Transcriptional regulation of the LDLR gene by citrus flavonoids has been implicated but, to our knowledge, not directly demonstrated. Here, using transfection vector constructs containing the upstream region of the LDLR gene, we show differences in both potency and efficacy in the induction of transcription, with peak stimulation of 5.3- to 7.5-fold of control at 150–160 µmol/L hesperetin and 3- to 3.8-fold of control at 10–20 µmol/L nobiletin. Hesperetin sustains induction, whereas nobiletin is inhibitory at high doses, resulting in an inverted-U dose response. The sterol regulatory element (SRE) in the LDLR gene upstream region plays a crucial role, because mutation of this site strongly attenuated induction in response to hesperetin or nobiletin. Thus, citrus flavonoids are likely to act through the SRE-binding proteins, with PMF initially activating these mechanisms at considerably lower concentrations than flavanones.

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