Alcohol-associated liver disease (ALD) contributes to more than 500,000 deaths worldwide annually. Two types of ALD, alcohol-associated hepatitis (AH) and alcohol-associated cirrhosis (AC), have a particularly poor prognosis and few treatment options.

The researchers analyzed liver tissues and liver biopsies from AH and AC patients and observed four significant changes in the proteins involved in biological processes associated with liver disease, including liver fibrosis or scar tissue, low albumin levels, white blood cell function and production of cardiolipin. These alterations may be adapted to serve as biomarkers to diagnose these conditions, assess the level of severity of AH and used as targets to develop new treatments.

“Many patients with ALD are unaware of the severity of their condition, and there are very few medical treatment options available,” said Irina A. Kirpich, associate professor of medicine at UofL, who led the study along with Jon Jacobs of Pacific Northwest National Laboratory in Richland, Washington. “This problem has intensified over time and the COVID-19 epidemic has exacerbated alcohol-related hospitalizations. There is a real necessity for the identification and development of biomarkers and treatments.”

Results of the study, which involved UofL researchers Kirpich, Professor Craig McClain, postdoctoral associate Josiah Hardesty and researcher Dennis Warner, were published in the July issue of the .

“This one-of-a-kind study and its novel proteomic dataset will provide a roadmap for the development of novel biomarkers and therapies for AH and AC,” Kirpich said. “We are optimistic that findings from this study will be utilized by investigators in the field for years to come and could help enhance current treatment strategies to improve patient outcomes and open the door to new paradigms and ideas to improve patient care.”

The UofL Hepatobiology and Toxicology Center was created in 2016 with an $11.5 million grant from the NIH to support unique research focused on liver injury and disease and toxicology. The center supports leading-edge research conducted by junior investigators with mentorship from senior researchers, as well as pilot projects and core laboratory facilities that support research across the university. The researchers’ goal is reducing the impact of many types of liver illness through prevention and the development of therapies.

Kentucky leads the nation in increases in cirrhosis-related deaths and in liver cancer-related deaths. According to research published in , mortality due to cirrhosis has been increasing in the U.S. since 2009, with the greatest increase in deaths from cirrhosis in Kentucky. Non-alcoholic fatty liver diseases affect approximately 25% of adults and 10% of children in the U.S.

“This vital research at the University of Louisville advances the health of Kentuckians and people throughout the world,” said UofL President Neeli Bendapudi. “Through this center, UofL researchers will continue to expand their work to find ways to prevent and treat liver illnesses, many of which today have no FDA-approved treatment.”

Researchers at the focus on liver injury, nutrition and gut-liver interactions as well as interactions between the liver and environment, toxicants and drugs. Their ultimate goal is to contribute to the prevention and treatment of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (a major cause of cirrhosis of the liver), alcoholic liver disease and liver cancer.

“This incredible cohort of researchers is discovering new ways to address the liver illnesses that afflict so many Kentuckians. I am thrilled that young researchers will continue to be supported with COBRE funding at UofL,” said Toni Ganzel, dean of the UofL School of Medicine.

In its first five years, four of the funded junior investigators in the UofL H&T Center received independent NIH research funding, making way for a new cohort of project researchers. The renewal of COBRE funding encourages a continuous supply of researchers in specialized areas of medicine and the search for new disease treatments.

“This unique thematic center is focused on liver injury, disease and toxicology. We evaluate critical barriers in our understanding of the development and progression of liver disease and we define potential therapeutic targets that could transform current practice,” said Craig McClain, associate vice president for health affairs and translational research and principal investigator for the UofL H&T Center. “This new phase will build on that success and extend and strengthen the scope of the program.”  

“To push past the limitations of existing therapeutics, you need COBRE infrastructure grants to establish cutting-edge biomedical research centers and capabilities,” said Joshua L. Hood, a project investigator in the UofL H&T Center. “The more of these capabilities we have, the more we can explore multidisciplinary frontiers in biomedical science to facilitate the development of new treatments for liver-related cancer and other diseases.”

Current projects supported by the center include:

• Yan Li, associate professor in the Department of Surgery, is investigating preventive strategies and possible mechanisms behind non-alcoholic steatohepatitis, a potential precursor of liver cancer.
• Joshua L. Hood, assistant professor in the Department of Pharmacology & Toxicology, is examining how very small membrane-bound compartments known as nanovesicles that are released by cancer cells influence immune function in liver cancer.
• Ming Song, assistant professor in the Department of Medicine, is studying the role of fructose consumption on the disruption of intestinal barrier function in non-alcoholic fatty liver disease.
• Smita Ghare, instructor in the Department of Medicine, is investigating how alcohol-induced changes in the liver contribute to liver inflammation and injury.

UofL has a legacy of liver research dating to the 1970s when faculty members began investigating a cluster of cases of hepatic angiosarcoma, a rare liver cancer caused by exposure to vinyl chloride in a polymer manufacturing facility in an area of West Louisville known as Rubbertown. UofL researchers worked with the community and industry to document and reduce the effects of toxicants on worker health. UofL still maintains a biorepository of blood and liver tissue specimens begun during that research that serves as a resource for investigators studying the effects of environmental exposures on the liver.

In addition to research, the center provides support for community health. During the epidemic of Hepatitis A and C in the last decade, center investigators helped create the Kentucky Hepatitis Academic Mentorship Program. This program helped to train more than 140 primary care providers in the diagnosis and treatment of Hepatitis C. Those diseases now are declining.

Craig McClain, MD, UofL’s associate vice president for health affairs/research, is the principal investigator and head of a team that has received a Centers of Biomedical Research Excellence (COBRE) grant from the National Institutes of Health to explore diseases of the liver — hepatobiology and toxicology.

“Dr. McClain and his team are among not only the nation’s leaders, but the world’s leaders when it comes to researching liver diseases,” said Gregory C. Postel, MD, UofL interim executive vice president for health affairs. “Receipt of this grant demonstrates the breadth of the program Dr. McClain has developed through the years and the importance of that work in our understanding the liver function, liver disease and how to combat it.”

The grant, which totals more than $11.5 million throughout five years, brings together experienced senior mentors and promising junior investigators from across the university  in collaboration with scientists throughout the nation and world to perform cross-cutting research on the unique topics of hepatobiology and toxicology. The research will evaluate clinical barriers in the understanding of the development and progression of liver diseases. Additionally, they will define targets for prevention and treatment that may transform current medical practice.

The researchers have four current areas of interest:

• Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis, a major cause of cirrhosis of the liver,
• Alcoholic liver disease,
• Environmental toxicology and liver disease, and
• Liver cancer.

Future areas of research include infectious and viral liver disease and drug-induced liver injury.

The liver is the largest internal organ. It plays a vital role in protein, carbohydrate, and fat, as well as micronutrient metabolism and it is the major site for drug and toxicant metabolism/detoxification.

Liver diseases are some of the most common health problems afflicting Americans. Approximately one-third of American adults and 10 to 12 percent of children in the United States have fatty liver disease as a consequence of overweight/obesity. This is by far the most common cause of abnormal liver tests in the nation. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of diseases involving hepatic fat accumulation, inflammation with the potential progression to scarring and cirrhosis over time.

Alcoholic liver disease (ALD) remains a major cause of mortality and morbidity in the United States, and ALD and NAFLD can proceed through the same pathway from simple fatty liver to cirrhosis in some patients. Importantly, there is no FDA-approved therapy for NAFLD or ALD. Liver cancer is the third leading cause of cancer deaths worldwide and is the fifth most common cause of cancer deaths in men in the United States.

“This effort will help ensure a pipeline of new investigators into liver biology and disease, as well as stimulate research into the field,” McClain said. “We will build upon the broad body of knowledge already existing (and) take that information into novel areas to create new methods for the prevention and treatment of liver disease.”