SCIENTISTS have identified the CDK4 protein as a trigger for the development of non-alcoholic fatty liver disease (NAFLD) and found that its inhibition can prevent the further development of early stages of the disease.
In a recent study by researchers at the Cincinnati Children’s Hospital Medical Center in Ohio, USA, high levels of CDK4 were found to occur in mouse models of NAFLD and human patients with fatty livers. An increased level of the protein was found to lead to later, more severe stages of NAFLD, such as fibrosis and hepatocellular carcinoma.
The researchers also found that blocking CDK4 in mice reduced hepatic steatosis, the first stage of NAFLD, involving build-ups of fat in the liver cells, and prevented progression to later stages. For the study, the team used flavopiridol and PD-0332991 to inhibit CDK4 and reduce the development of hepatic steatosis. One author of the study, Prof Nikolai Timchenko, Head of Liver Tumour Biology, Division of General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA, explained that: “This is the first study to show that CDK4 triggers development of NAFLD and that inhibiting this enzyme can both prevent and reverse the first step of the disease.”
NAFLD tends to develop in people who are overweight or obese and currently treatment of the disease is limited to weight-loss and lifestyle changes. Prof Timchenko emphasised the need for the development of safe and effective alternative treatments for NAFLD. He also explained that although currently undergoing clinical trials show promising results, there is also evidence of serious side effects, including the risk of developing liver cancer. Therefore, the CDK4 inhibitors used in the study have been identified as an important step towards a treatment halting the further development of hepatic steatosis. “Both of the CDK4 inhibitors we tested are approved by the FDA [US Food and Drug Administration] and in clinical trials for liver cancer, so it should be possible to initiate clinical trials for NAFLD with these drugs soon,” Prof Timchenko concluded.