Scientists at UofL, along with colleagues from Boston University and the University of Massachusetts Lowell, have identified perfluorooctane sulfonate (PFOS) as a potential environmental factor that worsens alcohol-associated liver disease.

PFOS is a man-made chemical belonging to the group known as per- and polyfluoroalkyl substances (PFAS), often referred to as “forever chemicals” because they do not readily break down in the environment or the human body. These substances have been used for decades in products such as non-stick cookware, water-resistant clothing, fast-food packaging, stain-resistant carpets and upholstery, and firefighting foams. Their extensive use has led to widespread contamination in the environment. show that PFAS can be detected in approximately 95% of Americans, sparking increasing concern about their long-term health effects.

At the same time, alcohol consumption remains a significant global health issue. , and its consumption continues to rise globally. In the U.S. alone, excessive alcohol use is responsible for approximately 95,000 deaths annually, making it one of the leading causes of preventable death and a major contributor to liver disease.

“Given the increasing prevalence of alcohol consumption and the widespread presence of PFAS in the environment, many individuals who drink alcohol may be inevitably exposed to these persistent pollutants. This makes it critically important to study how combined exposures to alcohol and environmental chemicals like PFOS might influence liver health,” said Matthew Cave, UofL professor of medicine and publication co-author.

Although it is well known that both alcohol and PFOS cause liver damage individually, little has been understood about their combined effects until now. , indicating that additional factors such as genetics, sex, microbiome and environmental exposures may contribute to individual susceptibility.

“This work helps explain why two people with similar alcohol consumption may experience very different liver outcomes,” said Frederick Ekuban, assistant professor of medicine at UofL and first author of the study. “Environmental exposures like PFOS may be the missing link.”

Using animal models, the researchers simulated real-world exposures to both alcohol and PFOS. The study showed that co-exposure to alcohol and PFOS significantly increased fat accumulation and markers of liver damage, as well as clear signs of disrupted metabolism and activation of genes and pathways predicted to be associated with oxidative stress and cancer development.

In short, the study demonstrates that PFOS exposure can significantly worsen liver damage when combined with alcohol consumption. While this research used high levels of alcohol to understand the underlying mechanisms, the findings reveal important biological pathways that warrant further investigation across different drinking patterns.

The research team also found that PFOS interferes with the liver’s ability to manage fats, disrupts its natural protective and repair systems and activates pathways that promote liver injury.

“While the liver typically has a remarkable capacity to recover from alcohol-induced stress, PFOS appears to push that resilience beyond its limits, resulting in compounded and more severe damage,” said Jennifer Schlezinger professor of environmental health at Boston University and co-author of the publication.

Perhaps most concerning, the team discovered that 60% of all PFOS exposure ended up concentrated in the liver, exactly where alcohol damage occurs.

Ongoing research at UofL is examining how other PFAS compounds may interact with alcohol, whether males and females respond differently to these exposures and what the long-term consequences of combined exposures might be. The team is also exploring whether targeted therapies can be developed to prevent or mitigate this type of liver damage.

Although more studies are needed, people can take practical steps now to limit their exposure to PFAS. These include:

• Choose stainless steel or cast-iron cookware instead of non-stick pans
• Use water filters, especially in areas near industrial zones
• Avoid stain-resistant treatments on furniture and carpets
• Reduce consumption of packaged fast foods and microwave popcorn.
• Select household products with PFAS-free labels

Given that liver disease affects millions of Americans and is becoming more prevalent worldwide, the findings of this research support growing calls for stronger regulation and oversight of persistent chemical contaminants. By better understanding the hidden interactions between environmental toxicants and lifestyle behaviors, scientists and policymakers may be better equipped to prevent and treat liver disease.

 Article by Sarah Jump

University of Louisville researcher Zhong-bin Deng has received a new grant from the National Institutes of Health to investigate how a high-fat diet contributes to these conditions and identify processes that may reduce liver inflammation and lead to new treatments.

Deng’s previous research revealed mechanisms in which dietary fat causes changes in the structure of epithelial cells, which comprise the lining of the walls of the intestines. When gaps form between these cells, toxins are allowed to move directly from the gut to the liver, where they cause an immune response and inflammation.

Building on this work, Deng, assistant professor in the Division of Immunotherapy within the Department of Surgery in the UofL School of Medicine, has been awarded $2 million from the NIH over five years to further investigate how these toxins cause the immune response in the liver, as well as test interventions that may reduce it.

“We are looking at how a high fat diet affects epithelial cells, allowing toxins to escape the gut and travel to the liver, leading to an immune response by macrophages in the liver and inflammation,” Deng said. “Also, we are trying to find a new therapy that could modulate the gut environment to control fatty liver disease.”

Deng’s research seeks to further understand the mechanism that leads to the gaps in the epithelial cells, which allow toxins produced by bacteria in the gut to move to the liver via the portal vein, known as the gut-liver axis. Deng and his team believe that the toxins cause the immune response of inflammation by changing Kupffer cells, white blood cells that reside in the liver. That inflammation can lead to liver cell damage.

“We propose that gut microbiota or the gut epithelial cells produce a signal that affects the Kupffer cells, causing inflammation in the high fat condition and may damage hepatocytes,” Deng said.

As part of the project, the researchers also will test whether an oligosaccharide found in human breast milk can be used to regulate the gut environment and mitigate the impact of the high fat diet on liver inflammation.

“We are trying to find out how to regulate this macrophage condition from an inflammation condition to an anti-inflammation condition,” Deng said.

“Dr. Deng’s new research evaluates highly novel aspects of nutrition in NAFLD,” said Craig McClain, professor and associate vice president for health affairs/research at UofL.

Jun Yan, director of the Division of Immunotherapy, said the research may lead to increased understanding of the causes of liver cancer.

“The research findings from this grant may also help understand how this type of liver inflammation leads to hepatocellular carcinoma, which causes approximately 30,000 deaths annually in the U.S.,” Yan said.

Results from Deng’s previous research in 2021.

“In environmental health, the study of liver disease is relatively new, particularly in the field of endocrine disrupting chemicals,” said Cave, associate professor of medicine in gastroenterology at the University of Louisville School of Medicine. “These chemicals, such as bisphenol-A (BPA), found in plastic drink bottles, may cause endocrine and metabolic diseases like diabetes and obesity, or make them worse.” 

With the NIEHS award, Cave plans to explore how any number of endocrine disrupting chemicals contribute to fatty liver disease. The flexible nature of the award allows him to redirect the research over the course of the funding, and adapt the work in light of new leads.

Cave is one of eight environmental health scientists receiving the new Revolutionizing Innovative, Visionary Environmental health Research (RIVER) Outstanding Investigator Award from the NIEHS. Awardees were selected based on their record of innovative and impactful research. Cave’s 8-year funding is the maximum awarded for this program. The new RIVER awards differ from the NIH’s traditional approach of funding projects designed to study specific aims, which can steadily produce new knowledge but may limit scientists when their results suggest new directions. Through RIVER, Cave will be able to explore novel directions of research in environmental liver disease.

“The RIVER program is designed to fund people, not projects. It gives outstanding environmental health scientists stable funding, time, and importantly, flexibility to pursue creative scientific ideas, rather than constantly writing grants to support their research programs,” said David Balshaw, PhD, chief of the NIEHS Exposure, Response and Technology Branch who leads the NIEHS team overseeing this initiative.

“This funding mechanism gives us the flexibility to study this evolving field and the freedom to pursue the hot leads as they develop,” Cave said. “I am very flattered to receive this award. It demonstrates the confidence the NIEHS has in my work.”

While the specific projects will evolve over time, Cave’s initial work will focus on exposures to polychlorinated biphenyls (PCBs) and vinyl chloride. PCBs are chemical compounds previously used in electrical equipment and other products. Although banned from production in 1979, PCBs do not readily break down and can remain in the environment. Vinyl chloride is used in the production of polyvinyl chloride (PVC), from which plastic pipes and other construction materials are formed. Both compounds are known to cause liver damage. Cave plans a multi-tiered research approach, beginning with cell cultures and animal models and then in humans.

As a framework for his research, Cave will establish the Environmental Liver Disease Revolutionizing Innovative, Visionary Environmental Health Research Program (ELD-RIVER), a unique integrative and collaborative research program including collaborations with academia, government agencies, industry, and scientific/medical societies. Cave and award co-investigator Juliane Beier Arteel, Ph.D., are collaborating with UofL’s NIAAA Alcohol Research Center, Diabetes and Obesity Center, and researchers in cardiology, biochemistry, pharmacology and toxicology, as well as the Environmental Protection Agency.

More information about Cave’s grant is below: 

The UofL Center is one of only 20 in the nation. It’s funding score for the grant was the best in the nation, and it is the only center with a nutrition focus.

“We are going to take a unique focus into organ injury associated with alcohol use,” said Dr. Gregory C. Postel, interim executive vice president for health affairs at UofL. “Our researchers are going to examine the interactive role of nutrition and alcohol in the deleterious, as well as beneficial, effects of alcohol on the human body.”

Through four different projects, the research team led by Dr. Craig McClain, associate vice president for translational research and associate vice president for health affairs/research, has three specific aims:

1. Facilitate interdisciplinary approaches and serve as a regional/national resource for the study of nutrition and alcohol-induced organ injury;
2. Provide a robust pilot project program and comprehensive education and research training in order to develop the next generation of alcohol investigators; and
3. Develop potential therapeutic targets/interventions for alcohol-induced organ injury based on the mechanistic research of the center and translate knowledge/interventions to the community.

“This funding will allow us to look at the problems that alcohol abuse causes, as well as the potential benefits of alcohol,” McClain said. “Our focus on dietary nutrition and abuse is unique. For example, only a small proportion of people who abuse alcohol will develop liver disease. We believe that the type of dietary fat intake is critical in the development of alcohol-induced organ injury.”

To find answers, the center will initially focus on four projects.

Project 1 will evaluate the role of dietary unsaturated fat in the development/progression of alcoholic liver disease.

Project 2 will evaluate alcohol-induced alterations in the gut-liver axis. Researchers will examine the role of histone deacetylases (HDACs) in both the intestine and liver in alcohol-induced gut-barrier dysfunction and steatohepatitis and the role of probiotics and dietary HDAC inhibitors in preventing/treating experimental ALD.

Project 3 will determine mechanisms by which maternal alcohol consumption causes mental retardation in the offspring. Researchers will evaluate epigenetic mechanisms by which alcohol induces apoptosis and teratogenesis, and by which the nutraceutical, sulforaphane, provides epigenetic protection.

Project 4 will evaluate mechanisms by which alcohol causes increased susceptibility to acute lung injury. They postulate that chronic alcohol intake triggers extracellular matrix remodeling resulting in “repavement” of lung tissue with a proinflammatory extracelluar matrix and that this process can be modulated by dietary intervention.

“Our studies are designed to look at a number of organ systems, not just the liver,” McClain said. “Additionally, we are very interested in gaining a better understanding of the role alcohol may play during fetal development and the mechanisms associated with fetal alcohol syndrome.”

The research team spans 13 departments at UofL in six schools/colleges.

“One of the keys to developing the breadth of information we hope to achieve is bringing together people with expertise in areas that often are not combined,” McClain said. “It is important that we look at these issues from a broad perspective if we are to examine the overall impacts of alcohol.”

Here is more information about the Alcohol Research Center: