Menin orchestrates hepatic glucose and fatty acid uptake via deploying the cellular translocation of SIRT1 and PPARγ

Background Menin is a scaffold protein encoded by the Men1 gene, which interacts with various transcriptional proteins to activate or repress cellular processes and is a key mediator in multiple organs. Both liver-specific and hepatocyte-specific Menin deficiency promotes high-fat diet-induced liver steatosis in mice, as well as insulin resistance and type 2 diabetic phenotype. The potential link between Menin and hepatic metabolism homeostasis may provide new insights into the mechanism of fatty liver disease.Results Disturbance of hepatic Menin expression impacts metabolic pathways associated with non-alcoholic fatty liver disease (NAFLD), including the FoxO signaling pathway, which is similar to that observed in both oleic acid-induced fatty hepatocytes model and biopsied fatty liver tissues, but with elevated hepatic Menin expression and inhibited FABP1. Higher levels of Menin facilitate glucose uptake while restraining fatty acid uptake. Menin targets the expression of FABP3/4/5 and also CD36 or GK, PCK by binding to their promoter regions, while recruiting and deploying the cellular localization of PPAR gamma and SIRT1 in the nucleus and cytoplasm. Accordingly, Menin binds to PPAR gamma and/or FoxO1 in hepatocytes, and orchestrates hepatic glucose and fatty acid uptake by recruiting SIRT1.Conclusion Menin plays an orchestration role as a transcriptional activator and/or repressor to target downstream gene expression levels involved in hepatic energy uptake by interacting with the cellular energy sensor SIRT1, PPAR gamma, and/or FoxO1 and deploying their translocations between the cytoplasm and nucleus, thereby maintaining metabolic homeostasis. These findings provide more evidence suggesting Menin could be targeted for the treatment of hepatic steatosis, NAFLD or metabolic dysfunction-associated fatty liver disease (MAFLD), and even other hepatic diseases.

Automated summary

The scaffold protein Menin, encoded by the Men1 gene, plays a crucial role in regulating hepatic energy uptake and metabolic homeostasis. It interacts with cellular energy sensors SIRT1, PPAR gamma, and/or FoxO1 to target downstream gene expression levels, maintaining metabolic balance. These findings provide new insights into the potential therapeutic targeting of Menin in hepatic steatosis, NAFLD or MAFLD, and other hepatic diseases.