Study identifies gene changes linked to liver scarring in non-alcoholic fatty liver disease

Researchers at Lund University, with international collaborators, have identified altered liver gene expression linked specifically to fibrosis in metabolic dysfunction-associated steatotic liver disease, offering fresh insight into how the condition progresses and where future drug development may intervene

Metabolic dysfunction-associated steatotic liver disease (MASLD) – previously called non-alcoholic fatty liver disease – affects around 30 per cent of adults worldwide and has become an increasingly important focus for liver research because of its close association with obesity, type 2 diabetes and other metabolic disorders. 

Although the condition can remain silent for years, it can progress to liver fibrosis, cirrhosis and can result in liver failure. A study led by Lund University, Sweden has now identified altered expression of specific genes in the livers of people with obesity, MASLD and liver fibrosis, a finding that may help to improve future disease management, prevention strategies and therapeutic development.

The work has added to efforts to understand the molecular changes that drive the transition from relatively early liver disease to more advanced and dangerous forms. MASLD describes a spectrum of liver abnormalities linked to metabolic dysfunction rather than alcohol use.

One of the most important warning signs in that spectrum is liver fibrosis, the build-up of scar tissue in the liver. Fibrosis can arise at any stage of MASLD and is widely regarded as a key prognostic marker because it signals a greater likelihood of progression to severe liver damage.

That progression matters clinically because early intervention can – in some cases – slow or reverse liver injury. By contrast, advanced disease is far more difficult to treat. MASLD is currently managed chiefly through lifestyle measures such as dietary improvement, increased physical activity and weight reduction. There is, however, still no established drug treatment that directly targets the disease process itself. That therapeutic gap has made it especially important to identify the biological mechanisms that underpin progression from simple fat accumulation in the liver to inflammation, fibrosis and metabolic dysfunction-associated steatohepatitis (MASH).

“MASLD has several stages. Prompt treatment can slow down or reverse liver damage at the earlier stages of the disease.

“Once the disease has reached the fourth and final stage, it is no longer possible to stop the progression. MASLD is currently treated with a healthy diet, physical activity and weight loss, but there is currently no medical treatment of the disease.

“In our study, we have identified a possible treatment target,” said Dr. Philipp Kaldis, professor of metabolic disorders and liver disease at Lund University Diabetes Centre, who led the study.

To investigate what distinguishes patients whose disease has progressed to fibrosis from those whose disease has not, the international team analysed samples from people with obesity in Australia ahead of undergoing bariatric surgery. The study included 109 participants, of whom 76 had early-stage MASLD and 33 had no signs of the disease. The researchers carried out gene expression profiling on liver samples and analysed metabolites in both liver tissue and blood, with the aim of building a clearer picture of the biological processes associated with fibrosis progression.

This approach enabled the team to map the molecular landscape of MASLD in people with obesity in much greater detail. They separated participants with MASLD into two groups for closer study:

• those with MASLD but no liver fibrosis
• those with MASLD plus fibrosis.

The researchers found that expression of specific genes associated with GTP-binding proteins was altered in the livers of individuals who had both MASLD and fibrosis. By contrast, comparable changes did not appear in individuals who had MASLD without fibrosis. The result suggested that these gene expression shifts may be linked not simply to the presence of fatty liver disease but more specifically to scarring development.

The team then moved beyond observational analysis to test whether the pathway might have functional significance. In experiments on human cells, the researchers used GTPase inhibitors and found that treatment reduced collagen secretion. Because collagen deposition is a central feature of fibrosis, that result provided experimental support for the idea that this pathway may contribute to scar formation in the liver. In practical terms, the finding raises the prospect that drugs designed to interfere with such altered signalling could one day help to prevent or reduce fibrosis in MASLD.

“In our study, we have managed to link the altered gene expression to liver fibrosis. We have already proceeded with studies where we [looked at] the mechanisms in detail to investigate whether we can establish a causal relationship.

“We hope that this knowledge may lead to novel treatments in the future. If researchers develop a drug that inhibits the gene expression from being altered – and this would reduce the formation of liver fibrosis – then this could be a novel treatment option,” said Kaldis.

The study’s collaboration began after Kaldis contacted Professor Matthew Watt at the University of Melbourne, Australia, in connection with another paper. That exchange led to discussion about whether an Australian patient cohort with MASLD could help to reveal how the disease progresses.

Dr. Hyungwon Choi at the National University of Singapore contributed the multiomics analysis, while Dr. Volker Lauschke at Karolinska Institutet, Stockholm, Sweden, provided three-dimensional cellular models derived from patients with MASH. Those models allowed the team to test and validate aspects of their findings experimentally, which strengthened the biological relevance of the observations.

Taken together, the findings offer a more refined view of how MASLD may shift into a more harmful state. Rather than treat fibrosis as a late and vague consequence of liver disease, the work points to specific molecular alterations that could help to identify patients at higher risk and – in time – offer a route to targeted intervention. That matters because MASLD often causes no obvious symptoms, which means many people remain unaware that their liver is under strain until significant damage has already occurred.

“The study would not have been possible without this collaboration. There is a great need for increased knowledge of how liver diseases can be prevented and treated.

“MASLD is a disease that typically causes no symptoms, which means that the disease can go undetected and progress to more serious stages.

“Of course, this is a major problem for individuals who already have other systemic diseases, such as type 2 diabetes,” said Kaldis.

Although further work will be needed to establish causality and determine whether the identified pathway can be translated into a safe and effective therapy, the study has provided a plausible treatment target in a disease area that has long lacked one.

For further reading please visit: 10.7554/eLife.109534.1