Ssu72-HNF4 alpha signaling axis classify the transition from steatohepatitis to hepatocellular carcinoma

Growing evidence suggests a mechanistic link between steatohepatitis and hepatocellular carcinoma (HCC). However, the lack of representative animal models hampers efforts to understand pathophysiological mechanisms underlying steatohepatitis-related HCC. We found that liver-specific deletion of Ssu72 phosphatase in mice, leads to a high incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis, but not HCC. However, loss of Ssu72 drastically increased the probability of HCC developing, as well as the population of hepatic progenitors, in various chemical and metabolic syndrome-induced HCC models. Importantly, hepatic Ssu72 loss resulted in the induction of mature hepatocyte-to-progenitor cell conversion, by dedifferentiation orchestrated by Ssu72-mediated hypo-phosphorylation of hepatocyte nuclear factor 4 alpha (HNF4 alpha), a master regulator of hepatocyte function. Our findings suggest that Ssu72-mediated HNF4 alpha transcription contributes to the progression of steatohepatitis-associated HCC by regulating the dedifferentiation potential of hepatocytes. Thus, targeting the Ssu72-mediated HNF4 alpha signaling that underlies the pathogenesis of steatohepatitis-associated HCC development could be a novel therapeutic intervention for steatohepatitis-associated HCC.

Automated summary

The loss of Ssu72 in the liver leads to nonalcoholic fatty liver disease and steatohepatitis, but not HCC. However, the absence of Ssu72 significantly increases the probability of HCC development and the population of hepatic progenitors in various induced HCC models.