CORVALLIS, Oregon. – Research from Oregon State University suggests that a pair of hop-derived compounds may help thwart a dangerous build-up of fat in the liver known as hepatic steatosis.
The results, published today in eLife, are important as it affects about a quarter of the people in the United States and Europe. While heavy drinking is often linked to liver problems, people with little or no history of alcohol make up that 25%, which is why their disease is known as non-alcoholic fatty liver disease, or NAFLD.
Insulin resistance, the hormone that regulates blood sugar levels, is a risk factor for NAFLD, as is obesity, a high-fat diet, and elevated blood lipids. The liver helps the body process nutrients and also acts as a filter for the circulatory system, and too much fat in the liver can lead to inflammation and liver failure.
In a mouse model study, Oregon state researchers, led by Adrian Gombart, showed that the compounds xanthohumol and tetrahydroxanthohumol, abbreviated as XN and TXN, can reduce the dietary accumulation of fat in the liver.
XN is a prenylated flavonoid produced by hops, the plant that gives beer its taste and color, and TXN is a hydrogenated derivative of XN.
In the study, 60 mice were randomly assigned to one of five groups – low fat diet, high fat diet, high fat diet supplemented with XN, high fat diet supplemented with more XN, and high fat diet supplemented with TXN.
The researchers found that TXN helped curb weight gain associated with a high-fat diet and also stabilized blood sugar levels, both factors that prevented the liver from building up fat.
“We have shown that TXN is very effective in suppressing the development and progression of diet-induced liver steatosis,” said Gombart, professor of biochemistry and biophysics at the OSU College of Science and senior researcher at the Linus Pauling Institute. “TXN appeared to be more effective than XN, perhaps because significantly higher levels of TXN can build up in the liver, but XN can also slow disease progression at the higher dose.”
The mechanism of action of the compounds is based on PPARγ, a nuclear receptor protein that regulates gene expression. PPARγ controls glucose metabolism and the storage of fatty acids, and the activated genes stimulate the formation of fat cells from stem cells.
XN and TXN act as “antagonists” for PPAR they – they bind to the protein without putting it into action, as opposed to a PPARγ agonist which would both activate and bind to it. The result of the antagonism in this case is less fat accumulation in the liver.
“Activated PPAR? stimulates lipid storage in the liver and our data suggest that XN and TXN block activation and greatly reduce the expression of the genes that promote lipid storage in the liver, ”explains Gombart. “These results are consistent with studies showing that weaker PPARγ agonists are more effective than strong agonists in treating liver steatosis. In other words, lower PPARγ activation in the liver can be beneficial. “
TXN accumulated better in the liver than XN, which may explain why it was more effective at reducing lipids, but the difference in tissue accumulation is not fully understood.
“It may be because XN is metabolized more than TXN by the host and its gut microbiota, but additional studies are needed to find out,” said Gombart. “While XN and TXN are effective preventive approaches in rodents, future studies must determine whether the compounds can treat existing obesity in humans. However, our results suggest that the antagonism of PPARγ in the liver is a logical approach to the prevention and treatment of nutritional liver steatosis and related metabolic disorders, and they support the advancement of XN and TXN as low-cost therapeutic compounds. “
Yang Zhang, Matthew Robinson, Donald Jump, and Carmen Wong of the OSU College of Public Health and Human Sciences also worked on this research; Gerd Bobe from the University of Agricultural Sciences; Cristobal Miranda and Fred Stevens from the College of Pharmacy; Malcolm Lowry, Thomas Sharpton, Claudia Maier, and Victor Hsu from the College of Science; and Christiane V. Löhr of the Carlson College of Veterinary Medicine.
The study was funded by the National Institutes of Health; the Linus Pauling Institute; the OSU College of Pharmacy; Hopsteiner, Inc .; and the OSU Foundation Bühler-Wang Research Fund.