A New Way to Rejuvenate the Liver?
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.
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.”
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.
Utpal Pajvani, MD, PhD, is a Herbert Irving Associate Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons.
Additional authors: Changyu Zhu (Columbia University Irving Medical Center), KyeongJin Kim (CUIMC), Xiaobo Wang (CUIMC), Alberto Bartolome (CUIMC), Marcela Salomao (Mayo Clinic, Phoenix, AZ), Paola Dongiovanni and Marica Meroni (Università degli Studi Milano and Fondazione IRCCS Ca’ Granda Ospedale Policlinico, Milan), Mark J. Graham (Ionis Pharmaceuticals, Carlsbad, CA), Katherine P. Yates (Johns Hopkins Bloomberg School of Public Health), Anna Mae Diehl (Duke University Medical Center), Robert F. Schwabe (CUIMC), Ira Tabas (CUIMC), Luca Valenti (Università degli Studi Milano and Fondazione IRCCS Ca’ Granda Ospedale Policlinico).
This work was supported by the National Institutes of Health (grants DK103818, DK105303, S10OD020056, and 5P30DK063608), Associazione Italiana per la Ricerca sul Cancro (grant 16888), American Liver Foundation (ALF Liver Scholar Award), American Heart Association (predoctoral fellowship 17PRE33120000). Human data came from the PIVENS trial, supported by NIH grants U01DK061734 and U01DK061730.
The authors declare that they have no competing financial interests.