Stopping This Certain Protein From Signaling Metabolic Stress Could Delay Aging, Obesity From Advancing to Fatty Liver Disease

Addressing unresolved issues of aging and obesity can help prevent fatty liver disease, a condition that has affected millions of people.

Stopping ZAK-Alpha From Triggering Metabolic Stress to Prevent Fatty Liver Disease

The most prevalent liver illness, nonalcoholic fatty liver disease, affects millions of people worldwide-100 million in the United States alone-and can eventually progress to liver cirrhosis and liver failure. It may result from the buildup of fat in the liver, fueled by gaining weight and aging.

The variables that lead to fatty liver disease have been found in a new study. Aging and weight increase can contribute to fatty liver because they put the body's cells under "stress," which produces too much of a substance called reactive oxygen species. These can harm cells and cause the body's "brown" fat to change into "white" fat, increasing the chance that the fat will be deposited in the liver.

Until recently, it was unknown what chemical processes led to the activation of stress, which in turn caused the conversion of fat. According to the authors, the trigger is a protein known as ZAK-alpha.

"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," said Simon Bekker-Jensen, a professor of cellular stress responses at the University of Copenhagen and a co-author of the paper.

The signal that initiates metabolic stress is interrupted if ZAK-alpha protein activity is inhibited. This could slow down the progression of metabolic disorders such as fatty liver caused by age and obesity. In mice and zebrafish, the researchers blocked the activity of the ZAK-alpha protein and discovered that this inhibited the progression of metabolic disorders.

"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," Bekker-Jensen explained.

The researchers added that mice are an excellent model of the human metabolic system because they can replicate many aspects of the current human lifestyle in the lab, such as an unhealthy diet high in calories and little exercise—mice that gain weight experience many of the same metabolic disorders that affect people.

The authors hoped that the study could aid in the development of medications and therapies for conditions like fatty liver as well as those brought on by age and obesity.

Fatty Liver Disease Medication

Nonalcoholic fatty liver disease is more common in those with type 2 diabetes and obesity. Roughly 75% of people who are overweight and 90% of people who are highly obese are impacted.

Overindulgence in drinking can also result in fatty liver disease. This is known as alcohol-associated fatty liver disease.

Unfortunately, there is no medication for the condition. One can only manage the condition by eating a healthy diet and exercising regularly.

Last year, the FDA rejected Intercept Pharmaceutical's second application to approve obeticholic acid (OCA) for the management of patients with stage 2 or 3 fibrosis in nonalcoholic steatohepatitis (NASH) or nonalcoholic fatty liver disease (NAFLD).

The FDA's decision was based on recommendations from the FDA Gastrointestinal Drugs Advisory Committee meeting. By a vote of 15 to 1, members suggested delaying approval until clinical outcome data were available. Even though OCA improved fibrosis in NASH patients with a moderate benefit over placebo based on the Intercept's clinical trial data, "there is uncertainty how the magnitude of changes in these surrogate endpoints may translate to meaningful changes in clinical outcomes," according to the FDA meeting briefing document. Notable safety concerns also included an increased risk of liver damage from drugs.

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