Diurnal Regulation of the Early Growth Response 1 (Egr-1) Protein Expression by Hepatocyte Nuclear Factor 4 alpha (HNF4 alpha) and Small Heterodimer Partner (SHP) Cross-talk in Liver Fibrosis

作者：Zhang Yuxia; Bonzo Jessica A; Gonzalez Frank J; Wang Li^*

来源：Journal of Biological Chemistry, 2011, 286(34): 29635-29643.

DOI：10.1074/jbc.M111.253039

Early growth response 1 (Egr-1) protein is a critical regulator of genes contributing to liver fibrosis; however, little is known about the upstream transcriptional factors that control its expression. Here we show that Egr-1 expression is tightly regulated by nuclear receptor signaling. Hepatocyte nuclear factor 4 alpha (HNF4 alpha) activated the Egr-1 promoter through three DR1 response elements as identified by trans-activation assays. Deletion of these response elements or knockdown of HNF4 alpha using siRNA largely abrogated Egr-1 promoter activation. HNF4 alpha activity, as well as its enrichment on the Egr-1 promoter, were markedly repressed by small heterodimer partner (SHP) co-expression. Egr-1 mRNA and protein were transiently induced by HNF4 alpha. On the contrary, HNF4 alpha siRNA reduced Egr-1 expression at both the mRNA and protein levels, and overexpression of SHP reversed these effects. Conversely, knockdown of SHP by siRNA elevated Egr-1 protein. Interestingly, Egr-1 mRNA exhibited diurnal fluctuation, which was synchronized to the cyclic expression of SHP and HNF4 alpha after cells were released from serum shock. Unexpectedly, the levels of Egr-1 mRNA and protein were highly up-regulated in Hnf4 alpha(-/-) mice. Both HNF4 alpha and Egr-1 expression were dramatically increased in SHP-/- mice with bile duct ligation and in human cirrhotic livers, which was inversely correlated with diminished SHP expression. In conclusion, our study revealed control network for Egr-1 expression through a feedback loop between SHP and HNF4 alpha.

• 出版日期2011-8-26
• 单位NIH