Novel candidate targets for the treatment of NASH
Nonalcoholic steatohepatitis is a global problem characterized by fat in the liver and commonly related with type 2 diabetes, hypertension, and high blood lipids. An estimated 30 to 40% of adults in the United States are affected, with approximately 20% of those affected in a more advanced stage known as nonalcoholic steatohepatitis, or NASH, which is characterized by liver inflammation and the potential development of cirrhosis and liver failure. NASH is also the world's fastest growing cause of liver cancer. Because advanced stages of NASH are caused by fibrosis or scarring, measures to prevent fibrosis are critical to NASH therapy. However, no drugs have been licensed for this purpose as of yet.
By comparing single nucleus sequencing data from mouse and human liver tissue in combination with mouse 3D imaging, a team of Scott Friedman researchers at the Icahn School of Medicine at Mount Sinai in New York identified novel drug candidates for the treatment of nonalcoholic fatty liver disease (NAFLD). The study, titled "An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis", was published in Science Translational Medicine.
The researchers employed single-nucleus sequencing of mouse and human liver tissue, as well as three-dimensional imaging of mice, to identify the critical hepatocytes-stellate cells that cause scarring in this study. They coupled a new technique to liver tissue hyalinization with gene expression analysis of individual stellate cells to demonstrate how scar tissue accumulates on these cells in NASH by tracking liver stellate cells.
The researchers used mouse models of NASH and human liver tissue from nine NASH patients and two controls in a single-core sequencing analysis.
To better understand the pathophysiological mechanisms and therapeutic strategies of NASH, a satisfactory genetically engineered or diet-induced mouse model that completely replicates the key physiological, metabolic, histological, transcriptomic, and cellular signal changes in human progressive NASH is required. Animal models of NASH may be divided into food induction, genetics, and a combination of several interventions. Typical models include:
l Methionine and choline deficiency (MCD) dietary model
l Choline-deficient, L-amino acid-defined supplemented, high-fat (CDAA) dietary model
l High-cholesterol (HCD) dietary model
l High sucrose and fructose dietary model
l Containing trans-fatty acid dietary model
l ob/ob mice
l db/db mice
l foz/foz mice
l SREBP-1c transgenic mice
l MUP-uPA transgenic mice
l Phosphatase and tensin homolog (PTEN) knockout mice
l Methionine adenosyl transferase 1A (Mat 1A) knockout mice
l LDLR knockout mice
l Combination models
The researchers discovered 68 possible pharmacological targets shared by both species. The researchers discovered that in advanced disease, a thick network, or reticulum, emerges between stellate cells, allowing these 68 new pairings to connect. The research also confirms the significance of one of the protein pairings, NTF3-NTRK3. Using a chemical created to disrupt NTRK3 in human cancer and repurposing it to demonstrate its promise as a novel drug against NASH fibrosis.
To conclude, the new information on hepatic fibrosis development implies that advanced fibrosis may have a distinct set of signaling combinations that promote scar formation, representing a hitherto unidentified collection of therapeutic targets.