Diet plays a critical role in the progression of NASH to liver cancer in mice
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. NAFLD patients are at a higher risk of developing non-alcoholic steatohepatitis (NASH), which causes severe and chronic liver inflammation, fibrosis, and liver damage. It is believed that a patient with NASH has a high risk of developing a form of liver cancer called hepatocellular carcinoma (HCC).
Other than lifestyle interventions, there is currently no approved treatment for NASH. Sometimes a liver transplant is the only cure.
While the risk factors for NASH (obesity, type 2 diabetes, and genetic mutations such as PNPLA3) and HCC (hepatitis B and C, excessive alcohol consumption, and cirrhosis) are well known, the precise mechanism for the progression of steatosis uncomplicated hepatic towards chronic inflammation, liver fibrosis, NASH and HCC are not known.
A recent study by researchers at the University of California San Diego School of Medicine found in a mouse model that when fed a Western diet high in calories, fat and cholesterol, mice gradually became obese, diabetic, and developed NASH, which progressed to HCC, chronic kidney disease and cardiovascular disease.
The results, published in the May 31, 2021 online edition of
Cellular and molecular gastroenterology and hepatology, showed that by simply changing the Western diet from a mouse model to a normal diet, where calories are derived from protein and carbohydrate rather than fat, without cholesterol, NASH and liver fibrosis were improved; and cancer progression and mortality avoided.
“While the mice who continued on the Western diet developed HCC and had an increased risk of death, 100 percent of the mice who discontinued the diet survived the duration of the study without developing HCC.” said Debanjan Dhar, PhD, study co-lead author and assistant professor in the Department of Medicine, Division of Gastroenterology, UC San Diego School of Medicine.
“This indicates that NASH and HCC may be a preventable disease and that diet plays a crucial role in disease outcome.”
In mice no longer receiving the Western diet, researchers also found decreased liver fat and improved tolerance to glucose – an indicator of diabetes – and several genes and cytokines affected by NASH returned to levels. and a normal function. Additionally, Dhar and his team discovered key changes in the gut microbiome that modulate the progression of liver disease.
“Although NASH is a disease of the liver, our results show that its development and progression is orchestrated by multiple organs.”
A surprising finding, the researchers said, was that when they changed the Western diet of mice with NASH to normal food, the effect was more pronounced on the liver rather than on total body weight.
“This could mean that slight changes in the liver could have profound effects on disease outcome,” said David Brenner, MD, senior co-author and vice chancellor of UC San Diego Health Sciences.
The researchers also compared results from mouse models to data sets from human patients, indicating that gene expression changes in mouse livers were similar to those of their human counterparts.
“Our animal model provides an important preclinical testing platform to study the safety and efficacy of drugs under development, as well as to test the reuse of other drugs already approved by the FDA for other diseases,” said said Dhar.
Co-authors include: Souradipta Ganguly, Linshan Shang, Ruoyu Wang, Yanhan Wang, Bernd Schnabl, Rob Knight, Sara Brin Rosenthal, Gibraan Rahman, Anthony Diomino, Tatiana Kisseleva, Mojgan Hosseini, and Mojgan Hosseini, all with UC San Diego; German Aleman Muench and Pejman Soorosh with Janssen Research and Development; and Hyeok Choon Kwon with National Medical Center, South Korea.
The research was funded in part by the National Institutes of Health (Grants DK120515, KL2TR001444 and 5P50AA011999), an ALF Liver Scholar award, the Southern California Research Center for ALPD and Cirrhosis.