They discover the mechanism underlying fatty liver

A pioneering study, conducted by researchers at City of Hope, one of the largest and most advanced cancer research and treatment organizations in the United States, has discovered how the liver activates a hormone that reduces the desire for sweets and alcohol. The findings could lead to new therapies for various conditions, such as fatty liver disease or MASLD (steatotic liver disease associated with metabolic dysfunction), which affects more than one billion people worldwide and increases the risk of developing type 2 diabetes and liver cancer.

In addition, scientists at this research center, a leader in diabetes and other life-threatening diseases, have also discovered how citrin deficiency (CD), a rare genetic disorder that prevents the liver from converting food into energy efficiently, can cause the accumulation of fat in the liver, even in thin people.

The study’s lead author, Dr. Charles Brenner, chair of the Chair of Diabetes and Cancer Metabolism at the Alfred E. Mann Family Foundation at City of Hope, noted that the disease fatty liver is more common in people with obesitybut hundreds of millions of thin people also unknowingly suffer from this condition that programs the liver to store fat instead of burning energy.

An internationally renowned biochemist, Brenner has spent decades discovering metabolic pathways and determining how they are Metabolic alterations influence health and disease. Two unusual facts surprised him: on the one hand, almost all CD patients are thin but have MASLD; and on the other hand, people with CD share an aversion to sweets. Knowing that the liver increases levels of the hormone FGF21 in multiple conditions of metabolic stress and that high doses of FGF21 cause an aversion to sweets and alcohol, Brenner hypothesized that specific stress in CD drives liver fat accumulation and FGF21 production.

“Similar to how the study of rare, hereditary cases of breast cancer in men led to the identification of key genes that drive common cases of breast cancer in women, we use DC as a model to understand why the liver generates fat instead of burning it in a lean state -explains-. “We discovered that the key lies in the accumulation of a small molecule called G3P that activates ChREBP, a protein that activates fat synthesis genes.”

The work, published in the magazine Nature Metabolismwas surprising because until then G3P had not been identified as the activator of ChREBP, and the conditions that induce FGF21, including both the ketogenic diet (the absence of carbohydrates) and the consumption of simple carbohydrates, had eluded understanding.

The findings suggest new therapeutic approaches to resolve MASLD. When G3P-ChREBP activates fat synthesis, it also inhibits fat burning, which could be controlled by drugs. In addition, doctors could prescribe G3P-based drugs to obtain the effects of FGF21, that is, reducing the appetite for sweets and, at the same time, activating fat-burning pathways.

The investigation, still ongoing, will be key to explore these treatment avenuesoffering hope to people with CD, lean individuals with fatty liver disease, and others for whom FGF21-based therapies may help lose weight and/or promote a healthier diet and lifestyle.

“Our primary goal is to transform our understanding of metabolic dysfunction into tangible benefits for people facing these interconnected diseases,” said Dr. Brenner. “By helping to discover new ways to treat the root causes, this study brings us one step closer to achieving that goal.”