A New Way to Rejuvenate the Liver?

In Brief

Fatty liver disease gets really serious, and possibly life-threatening, when the liver begins to accumulate scar tissue, a process doctors call fibrosis. 

But the events that trigger fibrosis in fatty liver have been unclear, impeding the development of drugs that could prevent the liver from scarring.

A recent study led by Utpal Pajvani, MD, PhD, at Columbia University Vagelos College of Physicians and Surgeons has identified the molecule Notch as a key instigator of liver fibrosis, a finding that could lead to new drugs. 

The study was published in Science Translational Medicine and recently highlighted in the New England Journal of Medicine.

Background

An estimated 100 million Americans have some form of nonalcoholic fatty liver disease (NAFLD). The condition was considered uncommon 30 years ago but has been rapidly increasing in parallel with the rising obesity rate. 

Although it’s possible to reverse NAFLD with weight loss, no treatments exist to reduce fibrosis or stop it from progressing. Fibrosis can lead to liver failure or cancer and is the primary determinant of mortality in NAFLD patients. 

Transplantation is the only clinical recourse when the liver fails. But with a limited supply of organs for transplantation, there is a desperate need for drugs to slow the progression of fatty liver disease.  

What the Study Found in Mice

Previous studies by Pajvani’s team showed that in mice and people with earlier stages of NAFLD, the liver has increased Notch activity. Cells use Notch to send signals, but Notch is usually inactive in the liver’s hepatocytes, the most abundant cell in the organ. 

In the new study, Pajvani’s team showed that Notch activation is not just an indicator of NAFLD, but rather triggers fibrosis. As proof, they showed that increasing Notch activity in hepatocytes could activate fibrosis, even in lean mice without fatty livers. And when Notch was disabled, fibrosis was blocked, even in obese mice with fatty livers.

The results suggested inhibiting Notch with a drug could prevent fibrosis, and Pajvani’s team found that an experimental drug that prevents Notch activity actually reversed fibrosis in mice.

What the Study Found in People

The study’s examination of a group of people with fatty liver disease suggests Notch triggers fibrosis in people in the same way it does in mice.

Among people in this group, the researchers found a correlation between the amount of fibrosis and the activity of Notch in the liver.  

Why the Finding Matters

The study is the first to link Notch activity in hepatocytes with liver fibrosis, and a drug that inhibits Notch could be a powerful way to treat NAFLD in people

“Our proof-of-principle experiments with an inhibitor of Notch demonstrate the potential of such drugs to address fibrosis,” Pajvani says. “Although our experiments were conducted in mice, we believe the data provide solid evidence to support the development of Notch inhibitors suitable for people with fatty liver disease.” 

Next Steps

Notch inhibitors are currently in development for cancer but are predicted to cause too many side effects to be used in people with fatty liver.  

Drugs that inhibit Notch only inside the liver’s hepatocytes—potentially delivered to the cells by nanoparticles or similar technology—would be needed to prevent those side effects.

The researchers are currently looking for other factors associated with Notch that could also be targeted to reverse or prevent fibrosis and reduce progression to liver cancer.