Transcriptional Regulation of Human and Rat Hepatic Lipid Metabolism by the Grapefruit Flavonoid Naringenin: Role of PPARα, PPARγ and LXRα

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 PPARα, PPARγ, and LXRα. We show it activates the ligand-binding domain of both PPARα and PPARγ, while inhibiting LXRα in GAL4-fusion reporters. Using TR-FRET, we show that naringenin is a partial agonist of LXRα, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPARα co-activator, PGC1α. The flavonoid activates PPAR response element (PPRE) while suppressing LXRα 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 LXRα-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 LXRα inhibitor.

Self-nanoemulsifying drug delivery system (SNEDDS) of the poorly water-soluble grapefruit flavonoid Naringenin: design, characterization,in vitroandin vivoevaluation

“…NRG has been reported to posses several effects on biological system such as antioxidant (Rice-Evans et al, 1996;Cao et al, 1997), anti-inflammatory (Manthey 2000), anticancer (Goldwasser, 2010), antifibrogenic (Lee et al, 2004) and antiatherogenic (Lee et al, 2001). The beneficial effects on human health are mainly due to their antioxidant activity and ability to chelate metals, to scavenge oxygen free-radical, to inhibit enzymes and to prevent oxidation of low-density lipoproteins (LDL) (Madsen et al, 2000;Yu et al, 2005).…”

Adaptive Cellular Stress Pathways as Therapeutic Targets of Dietary Phytochemicals: Focus on the Nervous System

“…Interestingly, the phytoestrogen daidzein protected cortical neurons in an experimental in vitro stroke model; this neuroprotection was due to an increased PPARg activity without direct binding to the receptor (Hurtado et al, 2012). The flavanone naringenin activates both PPARa and PPARg, and induces PPRE-driven gene expression in human hepatocytes (Goldwasser et al, 2010). A recent study reported that naringenin can protect the brain and prevent oxidative stress and NF-kB-mediated inflammation in a rat model of focal ischemic stroke (Raza et al, 2013).…”

Efecto del extracto etanólico de las hojas de Annona muricata L (guanabana) sobre Síndrome metabólico inducido en ratas

“…Otros estudios realizados con el flavonoide naringina han demostrado que normaliza los lípidos en diabetes e hipercolesterolemia a través de los receptores activados por proliferadores de peroxisoma (PPARs) tales como: PPARα, PPARγ y el receptor hepático X alfa (22) .…”