Study shows important role of hepatocyte adenosine kinase in NAFLD progression

Study shows important role of hepatocyte adenosine kinase in NAFLD progression

A study conducted by Texas A&M AgriLife Research provides compelling evidence for the important role of hepatocyte adenosine kinase in the progression of nonalcoholic fatty liver disease (NAFLD).

Chaidong Wu, Ph.D., was the corresponding author of a study on how hepatocyte adenosine kinase influences nonalcoholic fatty liver disease. (Photo by Texas A&M AgriLife)

The study, “Hepatocyte adenosine kinase promotes excessive fat deposition and liver inflammation,” appeared in September in the journal Gastroenterology.

Hepatocytes are cells that play a central role in liver function, including metabolism, detoxification, protein synthesis and innate immunity.

A key player in the proper functioning of hepatocytes is an enzyme called adenosine kinase, ADK. However, the current study shows that ADK can also drive the progression of liver disease.

Our aim was to investigate whether hepatocyte ADK promotes excessive fat deposition and liver inflammation.”

Chaodong Wu, MD, Ph.D., AgriLife Research Faculty Fellow, Texas A&M Department of Nutrition

Wu is also a Presidential Impact Fellow at Texas A&M University and corresponding author of the study.

Wu said NAFLD is strongly linked to obesity and progresses to an advanced stage when the liver develops obvious inflammatory damage.

This study suggested that hepatocyte ADK may be an important therapeutic target for the treatment of obesity and NAFLD.

“Research showed that hepatocyte adenosine kinase promotes excessive fat deposition and liver inflammation and is a key factor in the pathogenesis of nonalcoholic fatty liver disease,” he said. "There is already some evidence of how dietary changes can effectively help prevent or reduce the severity of NAFLD. If further research confirms the effects of dietary components on inhibiting adenosine kinase in hepatocytes, scientists could develop new approaches to treating this disease." .

About the study

The researchers examined how changes in ADK activity are related to the extent of liver inflammation and the amount of fat in the liver. The team studied mice that were genetically engineered to have either more or less ADK activity than normal.

The team fed the mice a high-fat diet for 12 weeks or a diet deficient in methionine-choline, which is known to contribute to liver damage, for five weeks.

On these diets, mice with reduced ADK activity in their hepatocytes had less fat and inflammation in the liver than controls. In contrast, mice with increased ADK activity had higher body weight and increased levels of body fat, liver fat and liver inflammation than normal mice.

In addition, the team conducted experiments to clarify exactly how ADK activity causes these effects.

Wu said the study involved analysis of cell-cell crosstalk using single-cell RNA sequencing, which was conducted with assistance from James Cai, Ph.D., a researcher in Texas A&M's Department of Veterinary Integrative Biosciences.

“Analysis of lipid profiles in mouse liver samples as part of the study showed an increased presence of lipids that promote mitochondrial dysfunction, which in turn leads to liver inflammation,” Wu said.

The team then analyzed ADK activity and liver health in human liver samples. As in mice, the data showed that reduced levels of ADK correlated with lower levels of NAFLD, while increased levels of the enzyme were associated with worsened liver steatosis and inflammation. The results also showed that ADK promotes excessive fat deposition and liver inflammation by suppressing the oxidation of fatty acids in liver cells.

“The amount of hepatocyte ADK protein was positively correlated with the degree of hepatic steatosis in livers of human subjects,” Wu said. “This novel finding highlights the pathological significance of the enzyme in human NAFLD.”

Diet and NAFLD

A 2020 study by Chaidong Wu, Ph.D., and his team showed that indole, a natural compound found in cruciferous vegetables, may be effective against nonalcoholic fatty liver disease. (Photo courtesy of Texas A&M Department of Horticultural Sciences)

Wu said the new study strongly suggests that an unhealthy diet, such as a diet rich in saturated fat, has a stimulating effect on increasing the amount of adenosine kinase protein in the liver.

“This in turn correlates positively with levels of obesity, NAFLD and systemic insulin resistance,” he said.

Wu previously examined the role of diet in NAFLD in a 2020 study conducted by scientists at AgriLife Research. The study published in Hepatology showed that indole -; a natural compound found in gut bacteria and cruciferous vegetables such as cabbage, kale, cauliflower and Brussels sprouts – could be effective in fighting the disease.

“This natural compound could lead to new treatments or preventive measures for NAFLD,” Wu said. “Healthy foods with high indole production capacity are important for the prevention of NAFLD and help improve the health of those affected.”

He said that preventing the development and progression of NAFLD may depend on nutritional approaches that ensure that gut microbes produce indole and other metabolites function effectively.

Source:

Texas A&M AgriLife Communications

Reference:

Li, H., et al. (2022) Hepatocyte adenosine kinase promotes excessive fat deposition and liver inflammation. Gastroenterology. doi.org/10.1053/j.gastro.2022.09.027.

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