The Grapefruit Flavonoid Naringenin Modulates Fatty Acid Metabolism in the Liver

The mechanism by which the grapefruit flavonoid naringenin regulates fatty acid metabolism at the molecular level is directly related to its effect on a group of nuclear receptors including PPAR-alpha (peroxisome proliferator-activated receptor alpha), PPAR-gamma (peroxisome proliferator-activated receptor gamma), and LXR-alpha (liver X receptor alpha).

Naringenin is a flavonoid that has been shown in previous research to have a bioactive effect on human health as an antioxidant, a free radical scavenger, an anti-inflammatory, a carbohydrate metabolism promoter, and an immune system modulator. This substance has also been shown to reduce oxidative damage to DNA in vitro. It is the predominant flavanone in grapefruit.

Naringenin has also been shown to reduce hepatitis C virus production by infected hepatocytes in cell culture. This effect seems to be linked to naringenin's ability to inhibit the secretion of very-low-density lipoprotein by the cells. In this regard, naringenin seems to protect LDLR-deficient mice from the obesity effects of a high-fat diet. It lowers plasma and hepatic cholesterol concentrations by suppressing HMG-CoA reductase and ACAT in rats fed a high-cholesterol diet.

In the current study, investigators at the Hebrew University of Jerusalem (Israel) and Massachusetts General Hospital (Boston, USA) studied the effect of naringenin on cultures of rat and human liver cells. They reported in the August 25, 2010, online edition of the journal PLoS ONE that naringenin regulated the activity of nuclear receptors PPAR-alpha, PPAR-gamma, and LXR-alpha. It activated the ligand-binding domain of both PPAR-alpha and PPAR-gamma, while inhibiting LXR-alpha in GAL4-fusion reporters. This effect resulted in the induction of a fasted-like state in primary rat hepatocytes in which fatty acid oxidation increased, while cholesterol and bile acid production decreased. The induction of PPAR-alpha and inhibition of LXR-alpha induced transcriptional changes in hepatocytes, upregulating genes important in fatty acid oxidation and down-regulating cholesterol and fatty acid synthesis.

"It is a fascinating find," said senior author Dr. Yaakov Nahmias, professor of engineering at the Hebrew University of Jerusalem. "We show the mechanism by which naringenin increases two important pharmaceutical targets, PPAR-alpha and PPAR-gamma, while blocking a third, LXR-alpha. The results are similar to those induced by long periods of fasting. Dual PPAR-alpha and PPAR-gamma agonists, like naringenin, were long sought after by the pharmaceutical industry, but their development was plagued by safety concerns. Remarkably, naringenin is a dietary supplement with a clear safety record. Evidence suggests it might actually protect the liver from damage."

Related Links:
Hebrew University of Jerusalem
Massachusetts General Hospital