CANBERRA, Jan. 13 (Xinhua) -- Blocking a key cellular enzyme, an approach thought to protect against fatty liver disease, may instead increase the risk of chronic liver damage and cancer as people age, Australian researchers warned on Tuesday.
Published in Science Advances, the study found that loss of the enzyme Caspase-2 drives abnormal growth in liver cells, triggering inflammation, fibrosis, and a significantly higher risk of liver cancer, according to a news release from Australia's Adelaide University.
The findings challenge growing interest in Caspase-2 inhibitors as a potential therapeutic strategy to treat and/or prevent fatty liver disease and highlight the need for caution when targeting this pathway, the release said.
Caspase-2 plays a critical role in maintaining the genetic stability of liver cells while also having an independent role in controlling fat levels in the liver, said lead researcher Loretta Dorstyn from the Center for Cancer Biology.
"Liver cells normally have extra copies of genetic material, known as polyploidy, and while this feature can help the liver cope with stress, our study shows that without the enzyme Caspase-2, abnormally high levels of polyploidy in the liver can be damaging," Dorstyn said.
In mice lacking the enzyme, or had a version of it that no longer worked, liver cells were abnormally large with an excessive amount of genetic and cellular damage, said the researchers.
"Over time, these mice developed chronic liver inflammation and characteristics of hepatitis-like liver disease, including scarring, oxidative damage and a type of cell death linked to inflammation," Dorstyn said, adding the aging animals were much more likely to develop liver cancer.
The research also shows that aging mice lacking functional Caspase-2 enzyme developed spontaneous liver tumors at much higher rates than normal mice, with up to four times the incidence of liver cancer, characteristic of hepatocellular carcinoma.
The findings overturn assumptions that inhibiting Caspase-2 is universally beneficial, showing that the enzyme is essential for removing damaged liver cells with age, without which, these cells build up and fuel cancer, Dorstyn said.
The authors said the research has important implications for drug development. ■
