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

Researchers have discovered new candidate drug targets for non-alcoholics fatty liver (NAFLD) using the latest technologies, including mononuclear sequencing of mouse and human liver tissue and advanced 3D mouse glass imaging to characterize major scar-producing liver cells.

The research was conducted by researchers at the Icahn School of Medicine at Mount Sinai.

Using these innovative methods, investigators uncovered a network of cell-to-cell communication resulting in wound healing as liver disease progresses. The findings, published in Science Translational Medicine, could lead to new treatments.

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

NASH is also the fastest growing cause of liver cancer worldwide. Since the advanced stages of NASH are caused by the accumulation of fibrosis or scarring, attempts to block fibrosis are the focus of efforts to treat NASH, but no drugs are currently approved for this purpose. say the researchers.

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

“We sought to understand the basis of this fibrous scarring and identify drug targets that could lead to new treatments for advanced NASH by studying hepatic stellate cells, which are the primary scarring cells in the liver,” he said. said the study’s lead author, Scott L. Friedman, MD, Irene Professor of Medicine and Dr. Arthur M. Fishberg, Dean of Therapeutic Discovery and Chief of Liver Diseases at Icahn Mount Sinai.

They added: “By combining this new approach to liver-in-glass imaging – an advanced tissue cleaning method that allows for in-depth analysis – with gene expression analysis in individual stellate cells, we have unveiled a any new understanding of how these cells generate NASH-like scarring is advancing to advanced stages.”

Researchers have found that in advanced disease, stellate cells develop a dense web, or mesh, of interactions among themselves that facilitate these 68 pairs of unique interactions not previously identified in this disease.

“We confirmed the importance of such a protein pair, NTF3-NTRK3, by using a molecule already developed to block NTRK3 in human cancers and repurposed it to establish its potential as a new drug to fight cancer. NASH fibrosis,” said first author Shuang (Sammi) Wang, PhD, an instructor in the Division of Liver Diseases. “This new understanding of fibrosis development suggests that advanced fibrosis may have a unique repertoire of healing-accelerating signals that represent a previously unrecognized set of drug targets.”

The researchers hypothesize that the communication circuits between cells change as the disease progresses, so some drugs may be more effective earlier and others at later stages. And the same drug may not work for all stages of the disease.

Researchers are currently working with chemists at Icahn Mount Sinai to further optimize NTRK3 inhibitors for the treatment of liver fibrosis. Next, the researchers plan to functionally screen all candidate interactors in a cell culture system, followed by testing in preclinical models of liver disease, as they did for NTRK3. Additionally, they hope to expand their efforts to determine whether similar interactions between fibrogenic cells underlie fibrosis of other tissues, including the heart, lungs and kidneys.

The article is titled “An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis”.

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