Newly-Identified Mechanism Could Be Used To Treat Fatty Liver Disease

One of the risks that come with aging and obesity is the development of metabolic diseases, including nonalcoholic fatty liver disease. Figuring out the intricacies of this process and how it could be stopped is far from an easy task, but researchers now believe they may have found the answers in a protein called ZAK-alpha.

Getting older or gaining excess weight can be stressful for some people, but it goes beyond our feelings – even our cells undergo “stress” with aging and obesity. This is in the form of overproduction of compounds called reactive oxygen species (ROS). Although these are produced during normal cellular metabolism, when there’s an excess of them, it can cause damage to our cells.

One of the consequences of this stress is the conversion of “brown” fat – which is packed full of mitochondria and responsible for regulating body temperature and helping to control blood sugar and insulin levels – into “white” fat. It’s too much of the latter that increases the chances of an excess level of fat being stored in the liver, known as nonalcoholic fatty liver disease (NAFLD).

NAFLD is thought to affect around 25 percent of the world’s population and though it often has no symptoms, it can lead to serious liver damage or cirrhosis if it continues to progress. As a result, scientists have been trying to uncover the factors involved in this progression, and a team led by Professor Simon Bekker-Jensen from the University of Copenhagen appears to have identified one of the key players.

“There is a protein called ZAK-alpha that ‘signals’ the rest of the metabolism system about the cells being stressed. This triggers a chain reaction leading to, among other things, fatty liver,” Bekker-Jensen explained in a statement.

The team confirmed this using cellular, mouse, and zebrafish models in which the ZAK-alpha protein was removed and the model then exposed to ROS, with the latter two models showing what the researchers suggest are promising results.

“Mice are a very good model for the human metabolism system… When mice become overweight, they develop largely the same metabolic diseases as seen in humans,” Bekker-Jensen explained. “Mice in which we deactivated the ZAK-alpha protein were much healthier than those with it. In old age, they were more active, had stronger muscles, and, importantly, did not develop various metabolic diseases.”

The researchers believe that the findings demonstrate ZAK-alpha could present a useful therapeutic avenue for NAFLD. “ZAK-alpha is a well-established drug target that can be inhibited with small molecules,” said Bekker-Jensen. “Therefore, we anticipate that this new knowledge will attract interest from numerous companies actively working on developing and testing drugs against metabolic diseases, including fatty liver.”

To reach a point where such a drug is on the market, the next step will be clinical studies. Time will tell if that comes to success, but the Bekker-Jensen is hopeful. “While there is already effective and affordable medicine for diabetes, I see great potential for fatty liver, which remains one of the most significant unresolved medical problems today.”

The study is published in Science.

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