Carbohydrate response element binding protein (ChREBP) correlation and contribution to NAFLD-mediated hepatocarcinogenesis

Backgroud Carbohydrate-response-element-binding-protein (ChREBP) is a glucose-mediated transcription-factor that is mainly expressed in liver & strongly involved in glycolytic & lipogenic-pathways [1, 2]. ChREBP has emerged as a pioneer-factor for regulation of de-novo lipogenesis (DNL), an important source of fatty-acids in the development of NAFLD (non-alcoholic-fatty-liver-disease) [3]. Previous studies from our group have suggested an associative role of ChREBP in development of hepatocellular-carcinoma (HCC) [4,5].

However, the molecular-pathogenesis of ChREBP-related-hepatocarcinogesis in response to high-fat-diet (HFD) in mice model remains unexplored. Here, we want to explore, role of PI3K/AKT/mTOR & RAS/RAF/MAPK signaling-pathways in liver-pathogenesis of our experimental mice models.

Methods Male C57BL/6J (WT), liver-ChREBP-KO (L-KO) & total body-ChREBP-KO (TB-KO) mice were maintained on either a HFD-(46%-fat) or control-diet (10%-fat) for 3 ,6 & 12-months to induce metabolic syndrome. Parallel mice-groups, with single-injection (at 4-weeks-old) of potent-hepatocarcinogen DEN (Diethylnitrosamine), were used as HCC-reference groups. Body-weight & blood-glucose were measured once a month. Post-perfusion, frozen liver-tissue samples were examined by western-blotting & RT-PCR.

Results We have investigated the role of PI3K/AKT/mTOR & RAS/RAF/MAPK pathways & their correlation with ChREBP-hepatic-deficiency. Our molecular-data suggest a notable downregulation in PI3K/AKT/mTOR (mTOR, AKT2, MAPK1) & RAS/RAF/MAPK pathway (HRAS, IRS1) as well as glycolysis (MLX, PKM) & lipogenesis (FASN) after ChREBP-knockout, compared to WT-mice, in both mice-models (HFD & DEN).

Conclusion Our present data further support the suggestion of a proto-oncogenic function of the transcription-factor ChREBP. Furthermore, our on-going study suggest the absence of HCC-development after liver-ChREBP deletion as well as downregulation of glycolytic & lipogenic-profile of the liver.

Publication History

Article published online:
23 January 2024