Excessive amounts of a protein called beta2-spectrin may put people at increased risk for nonalcoholic steatohepatitis (NASH), which is the leading cause of hepatocellular carcinoma (HCC), researchers said in a report published in Science Translational Medicine. Developing treatments to lower the protein may help reduce the incidence of both diseases.
Using mouse models, researchers found that subjects with no beta2-spectrin did not develop NASH when fed high-fat or western diets and those that were treated to develop HCC had fewer lesions than mice with normal levels of the protein. They also gained less weight from the unhealthy diets and had less body fat.
The researchers created small interface RNA (siRNA) to reduce the amounts of beta2-spectrin produced in liver cells and administered it to the mice with NASH; the treated mice showed improvements in NASH markers (i.e., serum fat and glucose levels). The researchers successfully reproduced the results in a 3-D culture model using human cells, and an siRNA drug approved to treat hepatic porphyria is already on the market.
The findings build on previous studies in which researchers identified a protein called TGF-beta that contributes to the development of nonalcoholic fatty liver disease (NAFLD), a precursor to NASH. About 25% of adults worldwide have NAFLD, and NASH has surpassed hepatitis C infection as the leading cause of HCC. Researchers have linked TGF-beta to several types of tumors and suspect it promotes metastasis.
“siRNA targeting beta2-spectrin reduced sterol regulatory element–binding protein activation in HCC cells, altered fatty acid metabolism- and fibrosis-associated gene expression in a human cell culture model of NASH, and attenuated diet-induced NAFLD in mice,” the researchers said. “The results identify how beta2-spectrin regulates sterol regulatory element–binding protein activity and support therapeutic targeting of beta2-spectrin.”