Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARalpha, PPARgamma and LXRalpha

PLoS One. 2010 Aug 25;5(8):e12399. doi: 10.1371/journal.pone.0012399.

Abstract

Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity, and atherosclerosis. Therefore, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health. The grapefruit flavonoid naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia, as well as inhibit the production of HCV. Here, we demonstrate that naringenin regulates the activity of nuclear receptors PPARalpha, PPARgamma, and LXRalpha. We show it activates the ligand-binding domain of both PPARalpha and PPARgamma, while inhibiting LXRalpha in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRalpha, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARalpha co-activator, PGC1alpha. The flavonoid activates PPAR response element (PPRE) while suppressing LXRalpha response element (LXRE) in human hepatocytes, translating into the induction of PPAR-regulated fatty acid oxidation genes such as CYP4A11, ACOX, UCP1 and ApoAI, and inhibition of LXRalpha-regulated lipogenesis genes, such as FAS, ABCA1, ABCG1, and HMGR. This effect results in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increases, while cholesterol and bile acid production decreases. Our findings explain the myriad effects of naringenin and support its continued clinical development. Of note, this is the first description of a non-toxic, naturally occurring LXRalpha inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bile Acids and Salts / biosynthesis
  • Cell Line
  • Cholesterol / biosynthesis
  • Citrus paradisi / chemistry*
  • Down-Regulation / drug effects
  • Fasting
  • Fatty Acids / biosynthesis
  • Fatty Acids / metabolism
  • Flavanones / pharmacology*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Ketone Bodies / metabolism
  • Lipid Metabolism / drug effects*
  • Lipid Metabolism / genetics
  • Liver / cytology
  • Liver / drug effects
  • Liver / metabolism*
  • Liver X Receptors
  • Orphan Nuclear Receptors / agonists
  • Orphan Nuclear Receptors / genetics
  • Orphan Nuclear Receptors / metabolism*
  • Oxidation-Reduction / drug effects
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Peroxisome Proliferator-Activated Receptors / genetics
  • Peroxisome Proliferator-Activated Receptors / metabolism*
  • Rats
  • Response Elements / genetics
  • Transcription, Genetic / drug effects*
  • Triglycerides / biosynthesis
  • Up-Regulation / drug effects

Substances

  • Bile Acids and Salts
  • Fatty Acids
  • Flavanones
  • Ketone Bodies
  • Liver X Receptors
  • NR1H3 protein, human
  • Nr1h3 protein, rat
  • Orphan Nuclear Receptors
  • PPAR alpha
  • PPAR gamma
  • Peroxisome Proliferator-Activated Receptors
  • Triglycerides
  • Cholesterol
  • naringenin