Coordinated Cross-Talk Between the Myc and Mlx Networks in Liver Regeneration and Neoplasia

BACKGROUND & AIMS: The c-Myc (Myc) Basic helix-loop-helix leucine zipper (bHLH-ZIP) transcription factor is deregulated in most cancers. In association with Max, Myc controls target genes that supervise metabolism, ribosome biogenesis, translation, and proliferation. This Myc network crosstalks with the Mlx network, which consists of the Myc-like proteins MondoA and ChREBP, and Max-like Mlx. Together, this extended Myc network regulates both common and distinct gene targets. Here, we studied the consequence of Myc and/or Mlx ablation in the liver, particularly those pertaining to hepatocyte proliferation, metabolism, and spontaneous tumorigenesis.& nbsp;METHODS: We examined the ability of hepatocytes lacking Mlx (MlxKO) or Myc thorn Mlx (double KO [DKO]) to repopulate the liver over an extended period of time in a murine model of type I tyrosinemia. We also compared this and other relevant behaviors, phenotypes, and transcriptomes of the livers with those from previously characterized MycKO, ChrebpKO, and MycKO x ChrebpKO mice.& nbsp;RESULTS: Hepatocyte regenerative potential deteriorated as the Extended Myc Network was progressively dismantled. Genes and pathways dysregulated in MlxKO and DKO hepatocytes included those pertaining to translation, mitochondrial function, and hepatic steatosis resembling nonalcoholic fatty liver disease. The Myc and Mlx Networks were shown to crosstalk, with the latter playing a disproportionate role in target gene regulation. All cohorts also developed steatosis and molecular evidence of early steatohepatitis. Finally, MlxKO and DKO mice showed extensive hepatic adenomatosis.& nbsp;CONCLUSIONS: In addition to showing cooperation between the Myc and Mlx Networks, this study showed the latter to be more important in maintaining proliferative, metabolic, and translational homeostasis, while concurrently serving as a suppressor of benign tumorigenesis. GEO accession numbers: GSE181371, GSE130178, and GSE114634.