Molecular and metabolic changes in human clear cell liver foci

Activation of the AKT/mTOR and Ras/MAPK pathways and the lipogenic phenotype are evident both in human hepatocellular carcinoma and in the rat model of insulin-induced hepatocarcinogenesis in the earliest preneoplastic lesions, i.e. clear cell foci (CCF) of altered hepatocytes. These CCFs have also been described in the human liver but characterization of molecular and metabolic changes are still pending. In this study, human sporadic CCFs were investigated in a collection of human non-cirrhotic liver specimens using histology, histochemistry, immunohistochemistry, electron microscopy and molecular pathological analysis. Human CCFs occurred in approximately 33 % of non-cirrhotic livers and stored masses of glycogen in the cytoplasm, largely due to reduced activity of glucose-6-phosphatase. Hepatocytes revealed an upregulation of the AKT/mTOR and the Ras/MAPK pathways, the insulin receptor, glucose transporters and enzymes of glycolysis and de novo lipogenesis. Proliferative activity was 2-fold higher than in extrafocal tissue. The CCFs of altered hepatocytes are metabolically and proliferatively active lesions even in humans. They resemble the well-known preneoplastic lesions from experimental models in terms of morphology, glycogen storage, overexpression of protooncogenic signaling pathways and activation of the lipogenic phenotype, which are also known in human hepatocellular carcinoma. This suggests that hepatic CCFs also represent very early lesions of hepatocarcinogenesis in humans.