HnRNP A1 mediates the activation of the IRES-dependent SREBP-1a mRNA translation in response to endoplasmic reticulum stress.

Growing evidences suggest the involvement of the endoplasmic reticulum (ER) stress in lipid metabolism and in the development of some liver disease such as steatosis. The transcription factor SREBP-1 modulates the expression of several enzymes involved in lipid synthesis. Previously, we showed that ER stress increased the SREBP-1a protein level in Hep G2 cells, by inducing a cap-independent translation of SREBP-1a mRNA, through an internal ribosome entry site (IRES), located in its leader region. Here, we report evidence that the heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) interacts with 5’-UTR of SREBP-1a mRNA, as an IRES trans-acting factor (ITAF), regulating SREBP-1a expression in Hep G2 cells and in primary rat hepatocytes. Overexpression of hnRNP A1 in Hep G2 cells and in rat hepatocytes increased both the SREBP-1a IRES activity and SREBP-1a protein level. Knockdown of hnRNP A1 by small interfering RNA reduced either the SREBP-1a IRES activity and SREBP-1a protein level. HnRNP A1 mediates the increase of SREBP-1a protein level and SREBP-1a IRES activity in Hep G2 cells and in rat hepatocytes upon tunicamycin- and thapsigargin-induced ER stress. The induced ER stress triggered the cytosolic relocation of hnRNP A1 and caused the increment of hnRNP A1 bound to the SREBP-1a 5’-UTR. These data indicate that hnRNP A1 participates in the IRES-dependent translation of SREBP-1a mRNA through RNA-protein interaction. Different content of hnRNP A1 was found in nuclei from liver of high fat diet-fed mice versus standard diet fed-mice, suggesting an involvement of ER stress-mediated hnRNP A1 subcellular redistribution on the onset of metabolic disorders.