Potential New Targets Identified in Non-Alcoholic Fatty Liver Disease: Research | Health

Researchers have discovered a new non-alcoholic candidate drug target fatty liver disease (NAFLD) uses state-of-the-art techniques such as mononuclear sequencing of mouse and human liver tissue and advanced 3D glass imaging in mice to characterize hepatocytes that generate significant scarring.

The study was led by researchers at the Icahn School of Medicine, Mount Sinai.

Utilizing these innovative methods, researchers discovered the following networks: Intercellular communication promotes scarring as liver disease progresses. The findings, published in Science Translational Medicine, may lead to new treatments.

Also read: Worrying signs that fatty liver is getting worse

characterized by liver fat NAFLD is a global threat, often associated with type 2 diabetes, hypertension and elevated blood lipids. An estimated 30-40% of adults in the United States are affected, and about 20% of these patients have a more advanced stage called non-alcoholic steatohepatitis (NASH), an inflammation of the liver. It is characterized by a high degree of scarring (liver cirrhosis) and liver failure.

NASH is also responsible for the fastest growing incidence of liver cancer worldwide. Advanced stages of NASH are caused by fibrosis or scarring, so attempts to block fibrosis are central to his NASH treatment, but there are currently no drugs approved for this purpose, the researchers said. said.

As part of the experiment, the researchers performed single-nucleus sequencing in parallel studies of both a mouse model of NASH and human liver tissue from nine subjects and two controls with NASH. They identified a shared number of 68 pairs of potential drug targets across the two species. Additionally, the researchers pursued one of these pairs by testing an existing anticancer drug in mice as a proof of concept.

“By understanding the basis of this fibrous scarring and studying hepatic stellate cells, we aimed to identify drug targets that could lead to new treatments for advanced NASH. Friedman, MD, Irene and Dr Arthur M. Fishberg Professor of Medicine, Chair of Therapeutic Discovery, Director of Liver Disease at Icahn Mount Sinai.

“By combining this novel grass river imaging approach (an advanced tissue clearing method that allows for greater insight) with gene expression analysis of individual astrocytes, we can explore how these cells generate scarring as NASH. We have uncovered a whole new understanding of the

The researchers found that in advanced disease, astrocytes develop a dense network or meshwork of interactions that facilitates these 68 unique interacting pairs that have not been previously identified in this disease. I discovered that

“We confirmed the importance of one such protein pair, NTF3-NTRK3, using a molecule already developed to block NTRK3 in human cancers, which has been shown to reduce NASH fibrosis and We reused it to establish its potential as a new drug to fight,” said lead author Shuang (Sammi ) Wang, PhD, instructor in the Department of Liver Disease. “This new understanding of fibrosis development suggests that advanced fibrosis may have a unique repertoire of signals that accelerate scarring, representing a previously unrecognized set of drug targets. suggests.”

Researchers hypothesize that the circuitry of how cells communicate with each other evolves as the disease progresses. Also, the same drug may not work for all stages of the disease.

Researchers are now working with chemists at Icahn Mount Sinai to further optimize NTRK3 inhibitors for the treatment of liver fibrosis. The researchers next plan to functionally screen all candidate interactors in a cell culture system, as they did with NTRK3, followed by testing in preclinical models of liver disease. In addition, we would like to extend our studies to determine whether similar interactions between fibrogenic cells underlie fibrosis in other tissues such as heart, lung and kidney.

The title of the paper is “Hepatic stellate cell autocrine signaling circuitry underlies advanced fibrosis in non-alcoholic steatohepatitis.”

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