New liver cell linked to MASH and a gene called Themis ^{CEFR B1}

The study, led by Jiandie Lin at the University of Michigan Life Sciences Institute, appears in the Journal of Clinical Investigation and focuses on metabolic dysfunction-associated steatohepatitis, or MASH. MASH is a severe form of metabolic dysfunction-associated steatitis liver disease (MASLD). MASLD affects 5% to 10% of the US adult population and can lead to cirrhosis and liver cancer.

The team analysed gene expression from individual hepatocytes in healthy and MASH liver samples. They confirmed the three usual zones of hepatocytes but also identified a new cluster of hepatocytes that appeared only in MASH. These cells showed strong signatures of cellular senescence, a stalled state in which cells stop dividing but do not die, and senescent cells can harm tissue function and increase inflammation.

Further analysis identified unusual activity of a gene called Themis. Themis normally encodes the protein THEMIS in T cells and is not active in healthy hepatocytes, but in both mouse and human MASH liver Themis expression was strongly increased and ranked among the top activated genes. To test Themis, researchers used mouse models: deleting Themis in hepatocytes made liver injury, senescence, inflammation and fibrosis worse, while raising THEMIS levels reduced senescence and improved protection.

Lead author Xiaoxue Qiu, formerly in the Lin lab and now at the University of Minnesota, said Themis is a key regulator of hepatocyte senescence. Additional authors are from the University of Michigan and the University of Pittsburgh School of Medicine. The research was supported by the National Institutes of Health, the American Heart Association and the UM Diabetes Research Center. All mouse procedures were approved by the Institutional Animal Care and Use Committee at the University of Michigan.