Journal of Nutrition OpenSOurce Diets- www.ResearchDiets.com

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
 QUICK SEARCH:   [advanced]


     


This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Online Supporting Material
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Morin, B.
Right arrow Articles by Holland, L. J.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Morin, B.
Right arrow Articles by Holland, L. J.
© 2008 American Society for Nutrition J. Nutr. 138:1274-1281, July 2008


Biochemical, Molecular, and Genetic Mechanisms

The Citrus Flavonoids Hesperetin and Nobiletin Differentially Regulate Low Density Lipoprotein Receptor Gene Transcription in HepG2 Liver Cells1–3,

Brian Morin4, LaNita A. Nichols4, Katherine M. Zalasky4, J. Wade Davis5, John A. Manthey6 and Lené J. Holland4,*

4 Department of Medical Pharmacology and Physiology and 5 Departments of Health Management and Informatics, and Statistics, University of Missouri School of Medicine, Columbia, MO 65212 and 6 USDA, Agricultural Research Service, Citrus and Subtropical Products Laboratory, Winter Haven, FL 33881

* To whom correspondence should be addressed. E-mail: hollandl{at}health.missouri.edu .

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.








Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]