Animal Model Shows Effects of Diet on Liver Diseases

Apart from lifestyle interventions, there are currently no approved treatments for nonalcoholic steatohepatitis (NASH). A liver transplant is sometimes the only remedy.

While risk factors for NASH—obesity, type 2 diabetes, and gene mutations such as PNPLA3—and hepatocellular carcinoma (HCC)—hepatitis B and C infections, alcohol overconsumption and cirrhosis—are well known, the precise mechanism of how simple fatty liver progresses to chronic inflammation, liver fibrosis, NASH, and HCC isn’t known.

A recent study led by researchers at University of California (UC) San Diego School of Medicine found in a mouse model that when fed a Western diet rich in calories, fat, and cholesterol, the mice progressively developed obesity, diabetes, and NASH, which progressed to HCC, chronic kidney disease, and CVD.

The findings, published in Cellular and Molecular Gastroenterology and Hepatology, showed that by simply changing the Western diet in a mouse model to a normal chow diet, where calories are derived from proteins and carbohydrates rather than fats, with no cholesterol, NASH and liver fibrosis were improved and cancer progression and mortality prevented.

“While the mice that continued on a Western diet developed HCC and had an increased risk of death, 100% of the mice that stopped the diet survived the length of the study without developing HCC,” says Debanjan Dhar, PhD, co–senior author of the study and an assistant professor in the department of medicine, division of gastroenterology at 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 the disease outcome.”

In mice no longer fed the Western diet, researchers also found a decrease in liver fat and improvement in glucose tolerance, an indicator of diabetes, and several genes and cytokines that were affected in NASH returned to normal levels and function. In addition, Dhar and his team found key changes in the gut microbiome that modulate liver disease progression.

“Although NASH is a liver disease, our results show its development and progression is orchestrated by multiple organs.”

A surprising finding, the researchers say, was that when they switched the Western diet of the mice with NASH to normal chow, the effect was more pronounced on the liver rather than on whole body weight.

“This could mean that slight changes in the liver might have profound effects on the disease outcome,” says David Brenner, MD, co–senior author and vice chancellor of UC San Diego Health Sciences.

Researchers also compared mouse model findings with human patient datasets, indicating that gene expression changes in mouse livers were similar to human counterparts.

“Our animal model provides an important preclinical testing platform to study the safety and efficacy of drugs that are currently being developed, as well as to test the repurposing of other drugs that are already FDA approved for other diseases,” Dhar says.

— Source: University of California San Diego Health