Heritage College scientist gets NIH grant renewed to study fatty liver disease

Aug 20, 2018

Sonia Najjar, Ph.D., speaks about her research into fatty liver disease, in the J.O. Watson Memorial Lecture during the 2018 Ohio Osteopathic Symposium.

A research project headed by Ohio University Heritage College of Osteopathic Medicine faculty member Sonia Michael Najjar, Ph.D., which aims to better understand how fatty liver disease can progress to cirrhosis by way of liver fibrosis, has received a four-year R01 research project grant for more than $1.74 million from the National Institutes of Health.

Najjar is a professor of biomedical sciences who holds the Osteopathic Heritage Foundation John J. Kopchick, Ph.D., Endowed Eminent Research Chair. She has a long and distinguished record of research focusing on obesity, diabetes, fatty liver disease and their cardiovascular complications. Her research has been continuously funded by the NIH, and she has also received funding from agencies and organizations including the American Diabetes Association, National Science Foundation and U.S. Department of Agriculture. Her current study, “CEACAM and insulin action,” builds on her past research, and the NIH funding, which runs from June 2018 to May 2022, is a competitive renewal of a grant that began in 2000.

“With this significant NIH award, Dr. Najjar continues to bring national prominence to the Diabetes Institute at Ohio University,” said Darlene Berryman, Ph.D., associate dean for research and innovation and executive director of the Institute. “Her ability to receive this award in a challenging fiscal environment is a testament to her reputation and innovative approach to research. And most importantly, the findings from her work could greatly improve human health.” 

Seeking treatments for a ‘new epidemic’

A description of the project’s public health relevance, as provided to NIH, states: “Fatty liver disease is the new epidemic. Uncontrolled, it progresses to nonalcoholic fatty liver disease.” Fibrosis, or thickening and scarring of liver tissue, “is an integral part of the progression to cirrhosis and the eventual need for liver transplantation,” the description adds. The project, it says, will aim to identify a mechanism leading to fibrosis, and to better understand how the condition develops. The hope is that this improved understanding will allow researchers to find targeted strategies to prevent fibrosis and liver injury, and lower the rate of fatty liver disease.

Non-alcoholic fatty liver disease is the fastest-growing cause of liver dysfunction in the United States, affecting more than 80 million Americans. It is associated with obesity, metabolic syndrome and type 2 diabetes, and its progressive form, nonalcoholic steatohepatitis, is associated with fibrosis of the liver that can progress into cirrhosis.

Patients with non-alcoholic fatty liver disease show significantly lowered levels of CEACAM1, a plasma membrane glycoprotein that Najjar has discovered to promote insulin clearance, and the severity of the disease corresponds to the extent of CEACAM1 reduction. While Najjar has extensively studied how reduced CEACAM1 leads to fat buildup in the liver and insulin resistance, the goal of the current study is to expand the focus to identifying pathways in the development of fibrosis that are dependent on CEACAM1 – an approach that may lead to the discovery of treatments to prevent progression of the disease.

Research takes a novel approach

Najjar explained that her research project represents a “paradigm shift” in its approach to hepatic fibrosis, which involves activation of liver stellate cells. While it is commonly believed that fibrosis emerges from hepatocyte (liver cell) injury, Najjar’s novel study shows that reduction of CEACAM1 in stellate cells themselves and in endothelial cells in the liver causes fibrosis independently of fat accumulation and insulin resistance.

The research will make use of genetically modified mice produced in Najjar’s lab, which have been engineered to spontaneously develop fibrosis without the need for any dietary, chemical or surgical interventions that have been experimentally used to explain how fibrosis develops in mice. In the past, Najjar said, the lack of animal models that could faithfully replicate the fatty liver disease state in humans, especially its associated fibrosis, has limited scientists’ ability to understand how nonalcoholic steatohepatitis develops.

“We generated these novel and unique animal models that exhibit spontaneously all of the features of the human disease, especially fibrosis, to investigate how the disease develops in humans,” she said. If she and her team can discover the details of a cause-effect relationship between lowered CEACAM1 levels and fibrosis, she added, “then we can therapeutically target the disease by targeting CEACAM1.” The question she seeks to answer: “Can we effectively modify CEACAM1 levels in order to prevent the disease and its progression?”

If so, this would be a significant breakthrough. “There is currently no FDA-approved therapy for NASH, or for fibrosis in particular,” Najjar noted. “We don’t understand how it develops – we need to do so in order to fight this disease that is becoming an epidemic.”