Fatty livers halt tumor-suppressing protein, increasing cancer risk

Researchers from the University of Texas Health Science Center at Houston are shining light on why fatty livers can significantly increase the risk of the organ developing cancer. (Pixabay)

Scientists have long known that fatty livers can significantly increase the risk of the organ developing cancer. Now, early research is shining light on why.

Researchers from the University of Texas Health Science Center at Houston (UTHealth), writing in the journal Cancer Research, found that a type of aggressive liver cancer known as hepatocellular carcinoma (HCC) in mouse models was more likely to develop than expected from previous models when they had fatty livers, specifically those associated with non-alcoholic fatty liver disease.

“In this study, we showed that under conditions of fatty liver, female mice were more likely to develop HCC than expected from previous models,” the authors wrote.

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The culprit: reduced P1-HNF4α activity, a tumor-suppressing protein that can boost the risk of aggressive HCC and comes about as the result of a chronic high-fat diet.

“Using an inducible knockout model of the tumor-suppressive isoform of hepatocyte nuclear factor 4 alpha ('P1-HNF4α') in the liver in combination with prolonged high fat (HF) diet, we found that HCC developed equally in male and female mice as early as 38 weeks of age,” the UTHealth authors wrote.  

“Similar sex-independent HCC occurred in the 'STAM' model of mice, in which severe hyperglycemia and HF feeding results in rapid hepatic lipid deposition, fibrosis [scarring], and ultimately HCC.”

“This study provides potential mechanisms for the growing incidence of liver cancer in both men and women that is linked to fatty liver disease,” said Kristin Eckel-Mahan, Ph.D., the study's senior author and an assistant professor with the Center for Metabolic and Degenerative Diseases at the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases at UTHealth.

Liver cancer used to be a relatively rare disease, but its instance has been rising in recent years. Alcoholism and infections such as hepatitis C have long been associated with greater liver cancer risks, but the authors argue that fatty livers, predominately due to obesity, are also responsible for this rise in both sexes, with reduced P1-HNF4α activity a likely leading cause.

The authors believe this can translate into human risk, despite only being in mouse models, and could help future researchers identify and modulate activity and possibly find therapeutic interventions.

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