Illustration of a liver bisected by the scales of justice, often associated with the Greek goddess Themis. Researchers found that mouse livers lacking the protein THEMIS showed greater liver injury and inflammation (left side), while increased THEMIS led to improved protection from liver injury and MASH (right side).
Image Credit: Rajani Arora, U-M Life Sciences.
Scientific Frontline: Extended "At a Glance" Summary: Themis-Expressing Hepatocytes and MASH Protection
The Core Concept: Researchers have identified a novel cluster of liver cells (hepatocytes) that specifically emerge during metabolic dysfunction-associated steatohepatitis (MASH). These cells exhibit unique gene expression and cellular senescence, acting as a critical regulator of liver disease progression.
Key Distinction/Mechanism: Unlike traditional hepatocytes that are classified into three zones based on location-specific functions, this new cell type is characterized by an arrested, senescent state and the unusual activation of the Themis gene. The THEMIS protein—typically active in T cells rather than healthy liver cells—acts as a protective adaptation to metabolic stress, suppressing harmful inflammation, preventing liver injury, and mitigating MASH severity when overexpressed.
Major Frameworks/Components:
- Hepatocyte Zone Classification: The established biological model dividing liver cells by anatomical location, contrasting with the newly discovered disease-associated cellular cluster.
- Cellular Senescence: A biological state in which cells permanently stall—neither dividing nor dying. While senescence often contributes to harmful tissue inflammation, the THEMIS pathway regulates this state to protect the liver.
- Themis Gene Pathway: The genetic signaling framework newly identified in liver cells. Encoding the THEMIS protein, this pathway serves as an adaptive, protective response against metabolic stress.
- MASH/MASLD Pathology: The clinical progression model tracking the transition from metabolic dysfunction-associated steatotic liver disease (MASLD) to the more severe steatohepatitis (MASH), fibrosis, and potential cirrhosis.
Branch of Science: Hepatology, Cell and Developmental Biology, Molecular Genetics.
Future Application: The discovery establishes the THEMIS pathway as a prime therapeutic target. Future pharmacological interventions could manipulate this disease-associated hepatocyte subtype and its signaling pathways to halt, manage, or potentially reverse severe liver damage and fibrosis.
Why It Matters: MASH is a severe condition affecting 5% to 10% of the U.S. adult population, often progressing to life-threatening complications such as cirrhosis and liver cancer. Identifying the protective mechanisms of this novel liver cell provides a critical new avenue for treating previously intractable metabolic liver diseases.
A newly discovered type of liver cell may hold clues for treating severe liver disease, according to a recent study from the University of Michigan Life Sciences Institute.
The findings, published in the Journal of Clinical Investigation, reveal a signaling pathway that can protect against metabolic dysfunction-associated steatohepatitis, or MASH. This more severe form of metabolic dysfunction-associated steatotic liver disease, or MASLD, affects 5% to 10% of the US adult population and leads to cirrhosis and liver cancer.
The liver is composed of more than a dozen different cell types, including both liver cells (or hepatocytes) and other cells, such as stromal and immune cells. Researchers in the lab of LSI faculty member Jiandie Lin study the ways these various cell types communicate and interact to maintain a healthy liver environment and how communications change during disease.
Recently, the team analyzed gene expression signatures from individual hepatocytes in both healthy and MASH liver samples to identify specific liver cell types that could point to disease risk.
“Traditionally, hepatocytes are divided into three zones based on location-specific gene expression patterns that are tailored to specialized functions,” said Lin, a professor of cell and developmental biology and senior author of the new JCI study. “What was a little bit surprising when we analyzed the data is that, in addition to these three groups of hepatocytes, we found a new cluster of cells with a unique identity. And that particular group of cells only showed up in the MASH liver.”
A prominent feature that differentiated these cells from other hepatocytes was that they displayed signatures of cellular senescence, a stalled state in which the cell no longer divides but also does not die. In this arrested state, senescent cells interfere with normal tissue function, increase harmful inflammation, and contribute to disease.
Further analysis revealed unusual activity from a gene called Themis. This gene, which encodes the protein THEMIS, is typically expressed in a type of immune cell called a T cell but is not active in healthy hepatocytes.
“But in both mouse and human MASH livers, Themis expression was strongly increased. It actually ranked as one of the top genes being activated,” Lin said. “So, the next question is: Is it good or bad? Is this increased THEMIS damaging the liver, or is the cell activating this pathway to help adapt to metabolic stress in MASH?”
To answer this question, the researchers compared liver health in normal mice with that of mouse models in which Themis was deleted specifically from hepatocytes. The livers with no THEMIS fared much worse, showing greater signs of liver injury, senescence, inflammation, and fibrosis. Conversely, when THEMIS levels were increased in hepatocytes, the team observed decreased senescence and improved protection from liver injury and MASH.
“It’s pretty exciting, because only a couple of other studies have identified this cell population, and not much was really known about what these cells are doing in disease,” said lead author Xiaoxue Qiu, a former researcher in the Lin lab who recently started her own lab at the University of Minnesota. “And now we are seeing that Themis is a key regulator of hepatocyte senescence, and that manipulating this subtype of disease-associated hepatocytes can have a major impact on disease progression.”
Lin believes the findings offer a starting point to identify additional drivers of liver damage and determine whether the THEMIS pathway can offer a therapeutic target for MASH.
Funding: The research was supported by the National Institutes of Health, the American Heart Association, and the U-M Diabetes Research Center.
Additional information: All procedures performed in mice were approved by the Institutional Animal Care and Use Committee at the University of Michigan and performed in accordance with institutional guidelines.
Published in journal: Clinical Investigation
Authors: Xiaoxue Qiu, You Lu, Yuwei Tang, Linkang Zhou, Yu-tung Lee, Ziyi Meng, Zhimin Chen, Fnu Pradeepa, Lanuza A. P. Faccioli, Zhiping Hu, Alejandro Soto-Gutierrez, Siming Li, and Jiandie D. Lin
Source/Credit: University of Michigan
Reference Number: Bio050426_01
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