Metabolic dysfunction–associated steatohepatitis (MASH) is a liver disease that often results from an unhealthy diet over many years. At some point, the liver is further harmed by inflammation and fibrosis. Researchers have now characterised what happens at the cellular level when liver function is impaired.
MASH is a very common liver disease that often results from many years of an unhealthy diet.
At some point, the liver begins to malfunction, and this can result in cirrhosis, liver cancer and death.
A new study shows what happens at the cellular level when scarring and inflammation harms healthy liver cells.
The discovery suggests how a specific type of cell is associated with MASH, how drugs that are already being developed may be able to counteract MASH and how gut hormones strive daily to keep the liver functioning – even though our diet and lifestyles tend to destroy it.
“Improving understanding of the mechanisms that control liver cell function and dysfunction will enable us to keep specific liver cells functional so that they do not contribute to the development of MASH,” explains a researcher behind the study, Kim Ravnskjær, Associate Professor, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense.
The research has been published in the Journal of Hepatology.
MASH is deadly
The development of MASH typically begins with fat from the body’s adipose tissue being absorbed by hepatocytes: the primary liver cells. This is called steatosis, and many people (more than one in four) have it to a greater or lesser degree. Nevertheless, steatosis and MASH in particular are mainly associated with obesity and type 2 diabetes.
At some point, the function of hepatocytes is impaired from all the fat they have absorbed and then they die and start an inflammatory reaction.
During the inflammatory stage, hepatic stellate cells are activated, and active stellate cells form scar tissue in the liver.
Excessive scar tissue accumulating in the liver over time leads to cirrhosis and an increased risk of liver cancer.
“The liver has great excess capacity, but at a certain point after many years of fat accumulation in the liver and the resulting inflammation it stops functioning properly as a result of the accumulated tissue damage. This is irreversible and can cause the liver to fail, requiring a liver transplant,” says Kim Ravnskjær.
Cells protect the liver but can also lead to disease
Kim Ravnskjær and colleagues wanted to map what precisely activates the hepatic stellate cells and thereby contributes to impaired liver function.
Hepatic stellate cells reside in the liver and regulate the flow of blood to the other liver cells in connection with meals. The cells also extract vitamin A, which can be toxic in excessive quantities, and then slowly release it into the body between meals.
“The idea behind the study was to understand what keeps the hepatic stellate cells inactive. If we can replicate this among people with liver disease, we may also be able to slow down or reverse MASH before it develops into the more serious stages,” explains Kim Ravnskjær.
Analysing the genetic expression of individual liver cells
The researchers used single-cell RNA sequencing and special analysis methods to map the genetic expression in each of tens of thousands of liver cells: their cellular fingerprints, so to speak.
The researchers investigated hepatic stellate cells from mice, some of which were fed a typical Western diet high in sugar, fat and cholesterol and others a healthy diet.
The researchers thereby identified the molecular basis for how hepatic stellate cells are activated as MASH develops, and they confirmed their findings in patients’ liver tissue.
Hepatic stellate cells are strictly regulated
The researchers drew two main conclusions. First, they found that transcription factor FXR, which is a bile acid receptor, is present in hepatic stellate cells and is especially active. This means that bile acids may affect hepatic stellate cells.
FXR is highly expressed in resting hepatic stellate cells, but this activity decreases as stellate cells themselves become activated and involved in scar tissue formation in MASH.
Kim Ravnskjær says that this observation is especially useful because a drug similar to the body’s bile acids and currently undergoing a Phase 3 (human) trial specifically targets FXR. The new results imply that this drug might inhibit scar tissue formation by directly counteracting the activation of the hepatic stellate cells.
“We found that increasing the activity of FXR would inhibit activation of the hepatic stellate cells and preserve their normal function, which is a target in MASH because it can help to inhibit scar tissue formation. Our results support this being possible in these Phase 3 trials,” says Kim Ravnskjær.
Gut hormones can be used as drugs
The study also found that hepatic stellate cells have many receptors of the G protein–coupled type on the surface that control their functioning.
FXR keeps the genes for these receptors activated so that the hepatic stellate cells can remain inactive.
Conversely, when FXR loses activity, the expression of the receptors also decreases, and the hepatic stellate cells are more easily activated.
However, FXR is not alone in influencing the G protein–coupled receptors.
Some gut hormones can keep the stellate cells inactive through these G protein–coupled receptors and limit them to their normal functions in the liver: regulating the flow of blood in the liver and harvesting vitamin A.
Gut hormones are secreted when we eat, and eating (healthily) may thereby help to keep the hepatic stellate cells inactive and not forming scar tissue.
“This points to the interesting perspective that people with MASH may be able to use similar hormones to stimulate the G protein–coupled receptors on the surface of the hepatic stellate cells and thereby inhibit the stellate cells’ harmful formation of scar tissue in the liver,” concludes Kim Ravnskjær.
