The insulin-like growth factor 2 (IGF2) mRNA-binding protein p62/IGF2BP2-2 as a promoter of NAFLD and HCC?

Non-alcoholic fatty liver disease (NAFLD) represents the most common hepatic manifestation of chronic liver diseases in developed countries. Since non-alcoholic steatohepatitis (NASH) is responsible for a large proportion of cryptogenic cirrhosis and cirrhosis represents the main risk factor for hepatocellular carcinoma (HCC), HCC is a severe complication of end-stage NAFLD. Recent evidence published in this journal showed the therapeutic potential of an inhibition of the chemokine (C-C motif ) ligand 2 (CCL2)/monocyte chemoattractant protein-1 (MCP-1) in NASH. The study by Baeck et al elegantly demonstrated that the pharmacological administration of an RNA oligonucleotide against MCP-1 ameliorates murine steatosis and inflammation. Since mice deficient of the MCP-1 receptor also showed attenuated fibrosis, MCP-1 was suggested as a critical link in the axis steatosis–inflammation– fibrosis. Here, we report that animals with a liverspecific overexpression of the insulin-like growth factor 2 (IGF2) mRNA-binding protein p62/IMP2-2/IGF2BP2-2 exhibit distinctly elevated Ccl2 expression levels (figure 1A) when fed a methionine–cholinedeficient (MCD) diet, which models all hepatic stages of NAFLD. Accordingly, in addition to elevated inflammatory gene expression, p62 transgenics had higher fat deposition (figure 1B) and an earlier onset and more pronounced manifestation of fibrosis than their wild-type littermates on MCD diet (figure 1B). These data further support a critical role for MCP-1 in NASH and NASH-induced fibrosis as suggested previously. The autoantigen p62 was originally isolated from a patient with HCC and was found to be overexpressed in HCC patients and in premalignant cirrhotic nodules. We previously reported that p62 transgenic animals on regular chow develop a fatty liver. Our new findings suggest that the lipogenic action of p62 on the MCD diet is facilitated by the induction of the lipogenic transcription factor Srebp1c (figure 1C). Interestingly, sterol regulatory element binding protein (SREBP) has also been reported to play a critical role in HCC lipogenesis and correlates with a poor prognosis in HCC. In order to elucidate the molecular mechanism of fibrogenesis in p62