Hepatocellular clear cell foci in ChREBP knockout and wild type mice after intraportal pancreatic islet transplantation – a long time experiment

Carbohydrate-response element-binding protein (ChREBP) has been shown to be an essential partner in carcinogenesis in non-cirrhotic liver. ChREBP is a glucose-dependent transcription factor mainly stimulating glycolysis and de novo lipogenesis and is also activated by the protooncogenic pathway of AKT/mTOR. In short time experiments of one and four weeks proliferation activity of clear cell foci (CCF) of altered hepatocytes was half as high in diabetic ChREBP-knockout mice as in wild type mice after intraportal pancreatic islet transplantation. CCF of ChREBP-knockout mice revealed much more glycogen storage and less lipid storage than CCF of WT mice, due to reduced gluconeogenotic glucose-6-phosphatase activity and decreased glycolysis (i.e. hexokinase II, aldolase) and diminished lipogenesis (i.e. fatty acid synthase).

To confirm these results in long time experiments of six months intraportal pancreatic islet transplantation was used again for hormonal-induced carcinogenesis in the liver of streptozotocin-induced diabetic wild type (WT; n(Tx)= 56; n(control)= 39) and ChREBP-knockout mice (KO; n(Tx)= 37; n(control)= 38).

Like in short time experiments CCF in WT either in KO mice developed downstream the transplanted islets. These differed morphologically. CCF in WT mice store slightly more glycogen and fat than normal liver tissue whereas CCF in KO mice reveal a massive glycogen storage without any storage.

In contrast, hepatocytes of extrafocal liver tissue showed more glycogen storage in diabetic WT than in diabetic KO mice in computer assisted image analysis of PAS reaction. In general, the glycogen content was less in diabetic than in non-diabetic WT and KO mice.

Frequency of CCF was higher in KO mice (41% vs. 22%), but proliferation activity – measured as Bromodesoxyuridin (BrdU) labeling index – seems to be lower in CCF and extrafocal liver tissue of KO in comparison to WT mice.

Furthermore, one large hepatocellular adenoma developed in a diabetic WT mouse after islet transplantation. No tumor was found in KO mice.

These previous results confirm short time experiments and show an important participation of ChREBP in proliferation and development of neoplasia in the liver.