Two New Studies Explore Treatments and Models for Fatty Liver Disease

Researchers from the University of Barcelona and the Massachusetts Institute of Technology (MIT) have published separate studies examining potential treatments and research models for metabolic dysfunction-associated steatotic liver disease (MASLD), a condition characterized by fat accumulation in the liver. The studies address different aspects of the disease: drug combination efficacy in animal models and tissue modeling for drug testing in human cells.

Study 1: Drug Combination in Animal Models

A study from the University of Barcelona investigated the effects of pemafibrate, a lipid-lowering drug, and telmisartan, a blood pressure medication, on MASLD in animal models.

Key Findings

The combination of pemafibrate and telmisartan reduced liver fat accumulation in rats and zebrafish larvae fed a high-fat, high-fructose diet.

• In rats, half-doses of each drug administered together were as effective as full doses of either drug alone.
• The treatment also lowered blood pressure and cholesterol levels in the animals.

Mechanisms

The study identified that telmisartan restored levels of the PCK1 protein in the liver, shifting metabolism away from lipid synthesis toward glucose synthesis. This effect was observed in early-stage MASLD without inflammation or fibrosis. Pemafibrate and telmisartan act through different biological pathways, suggesting a synergistic effect when combined.

Context and Limitations

• MASLD affects approximately one in three adults worldwide and is associated with increased risk of liver damage and cardiovascular disease.
• Treatment options are limited, and many experimental drugs have failed clinical trials due to safety concerns.
• Drug repurposing—using approved medications for new indications—can be faster and safer than developing new drugs.
• The research is based on animal studies. Clinical trials in humans are needed to confirm whether the benefits observed in animals translate to patients.

Statements

Marta Alegret, professor at the University of Barcelona and lead researcher, stated:

"We have focused on these phases with the aim of preventing the disease from progressing to more severe stages. But for a drug to be used in these early stages, it must have a good safety profile in humans."

Alegret added:

"Combination therapy with drugs acting on different pathogenic pathways may be a better strategy than monotherapy, thanks to possible synergistic effects and reduced toxicity related to the use of lower doses of each drug."

Next Steps

The research team plans to investigate the drug combination in more advanced disease stages, including liver fibrosis, and to develop animal models that combine liver disease with cardiovascular conditions to assess effects on atherosclerosis.

Study 2: Liver Tissue Model for Drug Testing

MIT engineers have developed a tissue model designed to replicate liver architecture, including blood vessels and immune cells, for the purpose of discovering new treatments for liver diseases. The findings were published in Nature Communications and Communications Biology.

Model Design and Capabilities

• The researchers' findings indicate that this model can replicate early-stage liver disease inflammation and metabolic dysfunction.
• This device has the potential to assist in identifying and testing new drugs for these conditions.
• The model is part of an ongoing initiative to utilize microphysiological systems for exploring human liver biology, which is challenging to reproduce in animal models.

Use in Testing Existing Drugs

In a separate recent publication, an earlier iteration of their liver tissue model was employed to investigate the liver's response to resmetirom, a drug that treats metabolic dysfunction-associated steatohepatitis (MASH), an advanced liver disease, with effectiveness observed in approximately 30 percent of patients.

The team observed that the drug can induce an inflammatory response in liver tissue, which might contribute to its variable patient efficacy.

Technical Details

The Communications Biology paper detailed research from the lab of Linda Griffith, a professor at MIT, using the LiverChip, a microfluidic device developed in the 1990s. The LiverChip provides a scaffold for cultivating 3D liver tissue models from hepatocytes, the liver's primary cell type. This chip is utilized by pharmaceutical companies for assessing potential adverse liver effects of new drugs. For the current study, the chip was modified to facilitate MASLD research.

Model Application

To develop a MASLD model, researchers exposed the tissue to elevated levels of insulin, glucose, and fatty acids. This process resulted in fatty tissue accumulation and insulin resistance, characteristics frequently observed in MASLD patients that can contribute to type 2 diabetes. After model establishment, the tissue was treated with resmetirom, a drug that simulates thyroid hormone effects to stimulate fat breakdown. The researchers observed that this treatment also increased immune signaling and inflammation markers.

Statements

Linda Griffith stated that while existing tissue models can predict liver toxicity for some drugs, there is a need for improved disease state modeling to identify and validate drug targets, and to determine optimal drug use timing during disease progression.

Dominick Hellen, lead author of the resmetirom paper, stated that the observed immune response was unexpected given resmetirom's primary objective of reducing hepatic fibrosis in MASH. He suggested this finding might inform understanding of why only a subset of patients respond positively to the drug, noting that further experiments are required to clarify the underlying mechanism.

Authorship

• Dominick Hellen was the lead author of the resmetirom paper, published in Communications Biology.
• Erin Tevonian and Ellen Kan were the lead authors of the Nature Communications paper on the new microphysiological system.

Disease Background

MASLD affects over 100 million individuals in the United States. MASLD patients may develop MASH, a more severe condition characterized by liver fibrosis. Resmetirom and semaglutide are currently the only FDA-approved medications for MASH.