Our livers play a huge role in our health. The liver regulates chemicals in the blood, filters toxins and wastes out of the body, breaks down fat, and even plays a role in the immune response. But in a large portion of society, an unhealthy lifestyle contributes to liver damage. For example, over 90% of obese individuals have signs of fatty degeneration related to their livers. An estimated 1/5 of these individuals also experience liver cell death and inflammation, also known as nonalcoholic steatohepatitis (NASH). But what causes this liver damage specifically? According to Medical XPress, researchers from the German Cancer Research Center explored this question. Ultimately, the researchers determined that dendritic cells called cDC1 cells cause this damage. Check out the full research findings published in Nature Medicine.

cDC1 Cells

According to Miltenyi Biotech, cDC1 cells are a type of dendritic cell, cells which are:

naturally located in all tissues, especially those at the interface between the body and the external environment, such as skin, lung, and intestine. They are also present in lymphoid organs where they activate T cells, thus initiating immune responses.

In particular, cDC1 cells begin initiating these responses when they recognize pathogens in the body.

The Research

To begin their research, the researchers questioned what immune or inflammatory cells helped influence NASH-related liver damage. First, they evaluated which immune cells they found in the liver, as well as how intense the damage was. Researchers started by feeding mice a high-fat, high-cholesterol, and low-nutrient diet. As the mice models developed NASH, researchers evaluated their liver cells. Using single-cell RNA sequencing, researchers determined that the mice livers had high cDC1 cell levels.

After finding high levels of cDC1 cells in mice models, researchers performed similar testing on human liver cells sourced during biopsies. They found a similar result. More so, the level of cDC1 cells directly correlated to the amount of liver damage.

Next, researchers evaluated cDC1 cells – and the influence on liver damage. First, they genetically modified mice models to lack cDC1 cells. In another experiment, researchers inhibited cDC1 in the liver. Again, both findings were similar. The lower level of cDC1 cells correlated with less liver damage. Additional findings include:

• NASH-related liver tissue damage changes how the hematopoietic system works within the bone marrow. While dendritic cells are normally replaced over a few days, this alteration allows for the continued and more frequent resupply of cDC1 cells.
• Overall, these cDC1 cells prompt T-cells, a type of immune cell, to act more aggressively. In addition to this over aggression, cDC1 also prompts T-cells to register more proinflammatory responses.
• Ultimately, the high levels of cDC1 cells, along with the altered T cell behavior, causes NASH progression and severe liver damage.

As a result, researchers question whether immunomodulating drugs could help inhibit NASH progression and reduce liver damage.

Nonalcoholic Steatohepatitis (NASH)

Nonalcoholic steatohepatitis (NASH) is a condition in which fat accumulates in the liver. Specifically, NASH occurs in non-drinkers or those who do not drink often. As fat accumulates in the liver, it can cause inflammation, fibrosis (scar tissue formation), and liver damage, preventing the liver from adequately functioning. Risk factors include having diabetes or high cholesterol, obesity, or an underactive thyroid or pituitary gland. Not all patients will experience symptoms. However, if symptoms do arise, they include:

• General malaise
• Jaundice (yellowing of the skin and eyes)
• Pruritus (intense itching)
• Unintended weight loss
• Fatigue
• Pain, particularly in the upper right abdomen
• Nausea and vomiting
• Confusion
• Appetite loss
• Swelling of the lower extremities
• Spider-like blood vessels
• Enlarged spleen
• Red palms
• Easy bruising and bleeding