It is estimated that about one in four individuals worldwide have nonalcoholic fatty liver disease (NAFLD), in which fat builds up in the liver. NAFLD can advance to inflammation and damage in the liver, a condition known as nonalcoholic steatohepatitis or NASH.

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 were published in the journal Hepatology in 2021.