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A map of liver cells provides insights that could boost search for NASH drugs

Non-alcoholic fatty liver disease
Using single-cell RNA sequencing, scientists have uncovered new cellular changes that could drive the progression of NASH. (Nephron/Wikimedia Commons)

Nonalcoholic steatohepatitis (NASH) is caused by a buildup of fat in the liver that can lead to cirrhosis and liver cancer. There’s still no effective therapy for the disease, and what exactly triggers its progression on the cellular level remains unclear.

Now a team of scientists led by the University of Michigan has created a detailed map of liver cells, showing how different cells communicate with each other. By comparing healthy and diseased livers, they also identified changes to these cells that could drive the progression of NASH. They hope the map will inspire new targets for drug development.

The findings, published in the journal Molecular Cell, are based on single-cell RNA sequencing. This technology allows scientists to analyze each cell type individually, rather than looking at a mixture of cells. Last year, researchers used the technology to build an atlas of the airway tissue, and along the way discovered a novel cell type called pulmonary ionocyte that appears to contribute to cystic fibrosis.

Jiandie Lin, the senior author of the new study, and colleagues applied the technology to profile non-parenchymal cells, which make up about 40% of the cells in the liver.

Using a mouse model of NASH, they found that the emergence of some hepatic macrophages is a hallmark of the disease. These immune cells were marked by high expression of TREM2, a scavenger receptor that engulfs and clears out dead cells. TREM2 has been implicated in several neurological disorders such as Alzheimer’s disease. But in this study, its expression was strongly associated with the severity of NASH: The more diseased the liver, the more TREM2 the cells produced, the team showed.

Lin’s team also discovered that star-shaped hepatic stellate cells—which are known to be involved in liver fibrosis—appear to serve as a hub of liver-cell signaling by producing what the researchers dubbed “stellakines.” Because the expression of these stellate cell-derived molecules was elevated in NASH, the researchers concluded that it likely represents a key characteristic of NASH development.

The NIH estimates around 30% to 40% of adults in the U.S. have nonalcoholic fatty liver disease (NAFLD) and around 3% to 12% have NASH, the more severe form of the two NAFLD types. Due to the sizeable market, biopharma companies are pouring their resources into developing an effective treatment.

Boehringer Ingelheim recently licensed a dual agonist of GLP-1 and FGF21 from South Korea’s Yuhan for $40 million upfront and committed up to $830 million in potential milestones. And Eli Lilly is turning its investigational diabetes drug tirzepatide, a dual GIP and GLP-1 receptor agonist, against NASH in a phase 2b trial.

Meanwhile, several academic teams continue to uncover clues about what drives NASH. For example, researchers led by the Translational Genomics Research Institute recently found that the expression of the gene AEBP1 increased during the activation of stellate cells.

Lin believes the type of single-cell analysis used in his team’s latest study could bolster NASH drug development. The technology could help “uncover new biology, new disease mechanisms, maybe even new therapeutic targets,” he said in a statement.