A team led by Jiandie Lin at the University of Michigan Life Sciences Institute reports in the Journal of Clinical Investigation the discovery of a previously unrecognised hepatocyte population in metabolic dysfunction-associated steatohepatitis (MASH), the severe form of MASLD. MASLD affects 5% to 10% of US adults and can progress to cirrhosis and liver cancer. The study aims to identify drivers of liver damage and possible therapeutic pathways.
The researchers performed single-cell gene expression analysis of hepatocytes from healthy and MASH livers. They validated the three classical metabolic zones of hepatocytes but also found a distinct cluster present only in MASH. Cells in this cluster exhibited strong signatures of cellular senescence, a state in which cells stop dividing, remain alive and promote inflammation that impairs tissue function.
Analysis showed unusually high activity of a gene called Themis. Normally Themis encodes the protein THEMIS in T cells and is inactive in healthy hepatocytes; in both mouse and human MASH samples Themis expression was strongly increased and ranked among the top activated genes. Mouse experiments tested Themis function directly:
- Deleting Themis specifically in hepatocytes led to worse liver injury, more senescence, greater inflammation and increased fibrosis.
- Conversely, raising THEMIS levels in hepatocytes reduced senescence and improved protection from liver injury and MASH.
Lead author Xiaoxue Qiu, now at the University of Minnesota, and colleagues note the THEMIS pathway could be a therapeutic target and a starting point to find other drivers of liver damage. The work 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 and followed institutional guidelines.
Difficult words
- hepatocyte — a liver cell that performs metabolic functionshepatocytes
- senescence — a state where cells stop dividing but survive
- fibrosis — scarring of tissue caused by excess connective tissue
- cirrhosis — long-term liver damage with scarring and dysfunction
- expression — production of a gene's RNA or protein product
- pathway — a series of biological steps producing an effectpathways
- encode — to specify the protein sequence from a geneencodes
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Discussion questions
- What benefits and risks might there be in targeting the THEMIS pathway as a therapy for MASH?
- How could the discovery of a MASH-specific hepatocyte population influence future research or treatment strategies?
- Given that MASLD can lead to cirrhosis and liver cancer, what priorities should researchers and clinicians have when developing new therapies?
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