A research team at Ajou University School of Medicine said a decrease in mitochondrial matrix caseinolytic protease P (ClpP) plays an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH) induced by a high-fat and high-fructose diet.
ClpP regulates the protein balance in mitochondria. NASH is a disease in which fat accumulates, and inflammation occurs in the liver due to continuous overnutrition, not alcohol, and worsens into obesity, simple fatty liver, hepatitis, and liver fibrosis.
According to the hospital, mitochondrial dysfunction is considered a pathogenic linker in the development of NASH and inappropriate mitochondrial protein-quality control, possibly induced by insufficiency of the ClpP, can potentially cause mitochondrial dysfunction.
The research team, led by Professors Kang Yup and Choi Sung-e of the Department of Physiology, aimed to investigate hepatic ClpP levels in a diet-induced model of NASH and determine whether supplementation of ClpP can ameliorate diet-induced NASH.
When the expression of ClpP was artificially reduced in mouse hepatocytes, mitochondrial function was impaired due to the decrease in mitochondrial membrane potential, increase in reactive oxygen species, and decrease in ATP (adenosine triphosphate).
Also, due to the dysfunction of mitochondria, the team confirmed that the stress signal in the hepatocyte, inflammatory signal, and the expression of inflammation-inducing factors increased while insulin signals decreased.
Conversely, when ClpP expression was increased in mouse liver tissue, high-fat and high-fructose diet-induced NASH was reduced.
Notably, the team confirmed an alleviation of high-fat, high-fructose diet-induced NASH when it administered A54556A compound, known as a ClpP activating substance, through an intraperitoneal injection.
"As Koreans diet becomes westernized, the number of NASH patients is expected to keep rising along with obesity and diabetes," Professor Kang said. "This study confirmed that steatohepatitis can be alleviated by regulating ClpP activity."
The team looks forward to further research in the future that will actually help treat patients, Kang added.
The Journal of Hepatology published the results of the study in its September issue, titled "Mitochondrial protease ClpP supplementation ameliorates diet-induced NASH in mice."