BOSTON—Findings published in PLoS ONE explain the myriad effects of naringenin, a flavonoid found in grapefruit as a non-toxic, naturally occurring LXR-alpha inhibitor (2010;5(8): e12399. DOI:10.1371/journal.pone.0012399). Naringenin has been shown to normalize lipids in diabetes and hypercholesterolemia. Disruption of lipid and carbohydrate homeostasis is an important factor in the development of prevalent metabolic diseases such as diabetes, obesity and atherosclerosis. As a result, small molecules that could reduce insulin dependence and regulate dyslipidemia could have a dramatic effect on public health.

Researchers demonstrated naringenin regulates the activity of nuclear receptors PPAR-alpha, PPAR-gamma and LXR-alpha, which play an essential role in metabolism regulation. It activates the ligand-binding domain of both PPAR-alpha and PPAR-gamma, while inhibiting LXR-alpha in GAL4-fusion reporters. Naringenin is a partial agonist of LXR-alpha, inhibiting its association with Trap220 co-activator in the presence of TO901317. In addition, naringenin induces the expression of PPAR-alpha co-activator, PGC1-alpha. The flavonoid activates PPAR response element (PPRE) while suppressing LXR-alpha 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 LXR-alpha-regulated lipogenesis genes, such as FAS, ABCA1, ABCG, 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.

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