DETROIT – Kezhong Zhang, Ph.D., assistant professor of molecular medicine and genetics and of immunology and microbiology in the School of Medicine at Wayne State University, was awarded $1.7 million by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health to explore how molecular elements in the body regulate the development of non-alcoholic fatty liver disease (NAFLD).
The liver is an irreplaceable organ responsible for processing foods into essential energy and nutrients. According to the American Liver Foundation, 25 percent of Americans suffer from NAFLD, which involves the buildup of excess fat in the liver. Fatty liver disease is typically attributed to the consumption of alcohol, but NAFLD is a form of fatty liver disease that occurs even if a person does not consume alcohol. The condition frequently precedes or coexists with obesity, Type 2 diabetes or cardiovascular disease.
Zhang aims to identify the mechanism that regulates CREBH (cyclic AMP-responsive element-binding protein H), a transcription factor he believes is closely associated with the progression of NAFLD. Transcription factors are molecules that either promote or block the body from interpreting the DNA codes that tell the body what kind of proteins it needs to produce.
“Recently, we have accumulated strong preliminary evidence that CREBH plays a crucial role in regulating hepatic lipid homeostasis under metabolic stress conditions,” Zhang said. In a previous study, Zhang and his colleagues found that when they removed CREBH from the animal body, the accumulation of fat was reduced in the liver but increased in the blood stream.
Zhang hypothesizes that an excess of saturated fatty acids or inflammatory stimuli activates CREBH to facilitate fat production and digestion. Because fat contents are stuck in the liver, CREBH activity is crucial for the excessive fat buildup that characterizes and propagates NAFLD.
“This project will not only define the molecular basis by which a novel stress-sensing protein factor regulates lipid metabolism, it will also be significant for designing new strategies to prevent and treat human non-alcoholic fatty liver disease and its associated metabolic syndromes,” said Zhang.
The first step in Zhang’s investigation is to identify the mechanism that causes fatty acids to activate CREBH. He will then decipher the molecular code that allows CREBH to control the amount of fatty acids in the liver. His final step will be to understand the involvement of CREBH in taking fatty liver disease to its more severe state, steatohepatitis.
Zhang is collaborating with School of Medicine colleagues Leonard Lipovich, Ph.D., assistant professor of molecular medicine and genetics and of and neurology; Todd Leff, Ph.D., associate professor of pathology; Bruce Berkowitz, Ph.D., professor of anatomy and director of WSU’s Small Animal MRI Facility. Zhang is also working with Stephen Duncan, D.Phil., Marcus Professor of Human and Molecular Genetics at the Medical College of Wisconsin; and Maria Isabel Fiel, M.D., professor of pathology at the Mount Sinai School of Medicine in New York City.