New discovery at the IOR for the treatment of hepatic disorders of abnormal lipid deposition

657adc5ff6f1a968a39fe7f835352689.jpg
d8c81ccc5740265acb0996fd79409a4b.jpg

Institutional Communication Service

25 January 2023

The Experimental Therapeutics group, directed by Prof. Carlo V. Catapano at the Institute of Oncology Research (IOR, affiliated to USI and member of Bios+), in collaboration with Prof. Jonathan Hall at the Swiss Federal Institute of Technology in Zürich (ETH, Zurich) identified a novel mechanism for the treatment of hepatic disorders of abnormal lipid deposition.

The excessive consumption of food rich in fat and obesity are associated with many types of cancers and their aggressiveness. Obesity is also a risk factor for cancer metastasis and resistance to pharmacologic treatments. This is especially worrying in industrialized countries, as approximately 25% of adults are clinically obese. Obesity also carries an increased risk for non-alcoholic fatty liver disease (NAFLD), a condition characterized by steatosis that occurs when the amount of fatty acids available exceeds the capacity for their dismissal in the liver. NAFLD can progress to a more aggressive stage, named steatohepatitis (liver cell injury and inflammation), and ultimately to cirrhosis and liver cancer. Changes in dietary lifestyles and early pharmacologic intervention are crucial for helping patients.

 

The discovery

In the study published in Nature Communications, the IOR and ETHZ teams identified novel mechanism for treating disorders characterized by abnormal lipid accumulation in the liver. Lekka, Civenni and colleagues discovered that metabolic reprogramming in the liver involves the Lin28/let-7 axis. Lin28 are RNA-binding proteins that control various microRNAs (let-7) and messenger RNAs. Lin28 proteins have a well-established role in stemness, pluripotency, and cancer, and therefore, Lin28 antagonists can be potent anticancer drugs.

The researchers at IOR and ETHZ found that inhibition of the Lin28/let-7 axis using the novel specific antagonist C1632 markedly improves lipid metabolism in hepatic cells reducing lipid accumulation in the cytoplasm, a typical hallmark of steatosis. Specifically, C1632 accelerates fatty acid usage and the production of ketone bodies generatedfrom fatty acids (ketogenesis). Moreover, C1632 limits lipid accumulation and NAFLD development in transgenic and high-fat diet-fed mice.

The work of Lekka and colleagues suggests that Lin28 inhibition may provide an alternative to dietary modifications and a controlled intervention for the treatment of liver disease, cancer, and other age-related inflammatory and metabolic disorders through reprogramming lipid metabolism and increasing ketogenesis.