CNIO study shows pro-inflammatory molecule IL-17A can be a key factor in the development of NASH and HCC -
NASH (NASH) is a serious liver conditions above hepatocellular carcinoma (HCC) and is currently incurable. A study in search of the Spanish National Cancer Centre (CNIO) shows that a pro-inflammatory molecule IL-17A, is a key factor in the development of this pathology, and stresses that blocking IL-17A or inhibiting cells that secrete IL-17A with drugs such as digoxin (antiarrhythmic agent) may be useful for preventing NASH in patients predisposed to develop HCC.
HCC is the most aggressive liver tumor and a major cause of morbidity in cancer. Several risk factors have been associated with this cancer and its early stages, but the molecular mechanisms underlying the carcinogenic process remain unclear.
non-alcoholic fatty liver disease (NAFLD), characterized by the accumulation of excessive fat, is prevalent among obese people, patients or people infected with the virus-diabetes, and it is a important risk factor for HCC development. However, all obese people are changing at the most severe form NASH, which has a significant inflammatory component.
"The fat accumulation (steatosis) by itself can not explain the occurrence of NASH. In contrast, inflammation determines the progress and results of the disease, since only 10% 20% of obese patients with fatty liver disease will eventually develop NASH, "said Nabil Djouder, leader of the study. That Djouder and colleagues found that NASH, which is currently incurable, is the result of several "hits" and that "the first step is DNA damage to promote inflammation caused by excess nutrients" .
working with different mouse models, the authors demonstrate in the latest issue of Cancer Cell how excess nutrients stimulate the expression of an oncogene called URI in the liver. URI -which is also upregulated in viral hepatitis- leads to DNA damage in hepatocytes, which triggers systemic inflammation and crosstalk between white adipose tissue and the liver that ends ultimately in NASH.
Where DNA damage occurs in hepatocytes, immune cells infiltrate the liver, especially Th17 cells which release pro-inflammatory molecule IL-17A. This molecule, which is a cytokine induced neutrophil infiltration of adipose tissue which leads to insulin and the release of fatty acids resistance, resulting in non-alcoholic steatohepatitis. "Type 2 diabetes seems to precede NASH and HCC," said Djouder.
The researchers also treated healthy mice with injections of IL-17A and observed how the first signs of NASH appeared after four weeks, which confirms its crucial role in the development of the disease . Moreover, Djouder and his team blocked IL-17A using various methods -antibodies and digoxin among others- and prevented the development of NASH and HCC.
In addition, the URI of expression and IL-17A were positively associated with nonalcoholic stetatohepatitis and HCC in obese, HVB and HCV patients. This finding should pave the way for a new prevention strategy for NASH and HCC in high-risk patients, particularly diabetes or infection with viral hepatitis.
"HCV treatment is a socio-economic challenge of our society that blocking IL-17A [...] with digoxin may provide a cheap and effective prophylaxis for hepatitis B and C infected patients with high risk for NASH and HCC, "concludes the newspaper.
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