Now, for the first time, researchers find that a protein called cdk4 occurs at higher levels in mouse models and human patients with the disease.Apart from lifestyle changes and weight loss, there are currently no effective or safe treatments for non-alcoholic fatty liver disease. Also, when they blocked the protein in mice, using drugs, it significantly reduced development of hepatic steatosis – the first stage of the disease.
The researchers found high levels of a protein called cdk4 in people with fatty livers.
The study, by Cincinnati Children’s Hospital Medical Center in Ohio, is published in the journal Cell Reports.
Senior author Nikolai Timchenko, a professor in the department of surgery at the University of Cincinnati and head of the Liver Tumor Biology Program at Cincinnati Children’s, says:
“This is the first study to show that cdk4 triggers development of NAFLD [non-alcoholic fatty liver disease] and that inhibiting this enzyme can both prevent and reverse the first step of the disease.”
The first stage of NAFLD – called hepatic steatosis – can progress to a condition called NASH (non-alcoholic steatohepatitis) and eventually cirrhosis or liver cancer.
NAFLD tends to develop in people who are overweight or obese, or who have diabetes, high cholesterol, or high triglycerides. It can also result from poor eating habits and rapid weight loss.
However, some people can develop NAFLD even without these risk factors. Estimates suggest up to a quarter of Americans have NAFLD.
NAFLD is the buildup of extra fat in liver cells that is not caused by alcohol. It is normal for the liver to contain some fat, but if 5-10 percent of its weight is fat, then it is classed as fatty liver.
Prof. Timchenko says new safe and effective treatments for NAFLD are needed. Currently, the only way to treat the disease is through weight loss and lifestyle changes.
He explains that while new treatments currently undergoing clinical trials are showing promising results, they are also showing evidence of serious side effects.
Blocking cdk4 prevented hepatic steatosis
In their study, the researchers found high levels of a protein called cdk4 – which is triggered by a high-fat diet – in mouse models of NAFLD and in human patients with fatty livers.
In another part of the study, the team found blocking cdk4 disrupted the pathways and prevented the development of hepatic steatosis in mice that would normally develop it when raised on a high-fat diet.
The increase in cdk4 causes a chain of events through certain pathways that result in hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC or liver cancer), note the researchers.
They also found that inhibition of cdk4 in mouse livers with existing steatosis reversed the steatosis.
The inhibitors they used in the study were flavopiridol and PD-0332991.
The authors conclude that the critical finding of their study was to identify the elevation or activation of cdk4 as a key event in the development of NAFLD.
They suggest this finding – together with further work with cdk4 inhibitors – will likely offer strong evidence to support use of cdk4 inhibitors as a treatment that stops the liver developing steatosis, and even reverse existing steatosis.
“Both of the cdk4 inhibitors we tested are approved by the FDA and in clinical trials for liver cancer, so it should be possible to initiate clinical trials for NAFLD with these drugs soon.”
Prof. Nikolai Timchenko
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