Xanthohumol, a prenylated flavonoid produced by hops (Humulus lupulus), and its synthetic derivative, tetrahydroxanthohumol, can mitigate the diet-induced accumulation of fat in the liver known as hepatic steatosis (fatty liver disease), according to new research from Oregon State University.

Non-alcoholic fatty liver disease (NAFLD) is a major global health threat characterized by excessive hepatic lipid droplet accumulation with a history of little or no alcohol consumption,” said Oregon State University’s Professor Adrian Gombart and his colleagues.

“About one-quarter of the US population suffers from NAFLD, with rates in the rest of the world ranging from 14% in Africa to 32% in the Middle East.”

“The continuing obesity and diabetes epidemic drives increasing rates of NAFLD.”

“Unfortunately, no FDA-approved drugs exist for its treatment. Sustained healthy lifestyle changes and weight loss are the only interventions proven effective in preventing the onset and progression of NAFLD.”

“Thus, there is a critical need for novel and effective interventions.”

The objective of the current study was to determine the effect of xanthohumol (XN for short) and tetrahydroxanthohumol (TXN) on lipid accumulation in the liver.

For the study, 60 mice were randomly assigned to one of five groups – low-fat diet, high-fat diet, high-fat diet supplemented by XN, high-fat diet supplemented by more XN, and high-fat diet supplemented by TXN.

The researchers found that TXN helped put the brakes on the weight gain associated with a high-fat diet and also helped stabilize blood sugar levels, both factors in thwarting the buildup of fat in the liver.

“We demonstrated that TXN was very effective in suppressing the development and progression of hepatic steatosis caused by diet,” Professor Gombart said.

“TXN appeared to be more effective than XN perhaps because significantly higher levels of TXN are able to accumulate in the liver, but XN can slow progression of the condition as well, at the higher dose.”

The mechanism behind the compounds’ effectiveness involves a nuclear receptor protein called peroxisome proliferator activated receptor gamma (PPARγ).

PPARγ controls glucose metabolism and the storage of fatty acids, and the genes it activates stimulate the creation of fat cells from stem cells.

XN and TXN act as antagonists for PPARγ — they bind to the protein without sending it into action, unlike a PPARγ agonist, which would activate it as well as bind to it. The upshot of antagonism in this case is less fat collecting in the liver.

“Activated PPARγ in liver stimulates storage of lipids and our data suggest that XN and TXN block activation and greatly reduce expression of the genes the promote lipid storage in the liver,” Professor Gombart said.

“These findings are consistent with studies that show weaker PPARγ agonists are more effective at treating hepatic steatosis than strong agonists. In other words, lower PPARγ activation in the liver may be beneficial.”

TXN was better at accumulating in the liver than XN, which may explain why it was more effective in reducing lipids, but the difference in tissue accumulation is not fully understood.

“It may be because XN is metabolized by the host and its gut microbiota more than TXN is, but additional studies are needed to figure that out,” Professor Gombart said.

“Also, while XN and TXN are effective preventative approaches in rodents, future studies need to determine if the compounds can treat existing obesity in humans.”

“But our findings suggest antagonism of PPARγ in the liver is a logical approach to prevent and treat diet-induced liver steatosis and related metabolic disorders, and they support further development of XN and TXN as low-cost therapeutic compounds.”

could play a role in the onset of diabetes 2 and various other diseases.

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