Upregulation of Stromal‐derived Factor‐1 by Hypoxia Requires Hypoxia‐Inducible Factor‐1α and Transforming Growth Factor‐1

Abstract

Following both acute and chronic liver injury, expression of the chemokine stromal‐derived factor‐1 (SDF‐1), or CxCl12, is upregulated and plays a vital role in the activation of down‐stream signaling pathways implicated in either driving hepatic injury progression or leading to its repair. For example, while SDF‐1 has been implicated in promoting tumor growth and metastasis in patients with hepatocellular carcinoma, in acute injuries it may play an important role in liver regeneration. This suggests SDF‐1 may represent a novel target for therapeutic intervention in both acute and chronic liver diseases. However, the mechanism by which SDF‐1 is upregulated following hepatic injury is not fully known. The present study determined whether the transcription factor, hypoxia‐inducible factor‐1α (HIF‐1α), regulates SDF‐1 in primary mouse hepatocytes. To activate HIF‐1α in vitro, primary hepatocytes were incubated for 72 hrs in either room air or hypoxic (1% O2) conditions. Under hypoxic conditions, SDF‐1 mRNA levels were upregulated after 72 hr in WT mouse hepatocytes, an effect that was prevented in hepatocytes isolated from either HIF‐1α or HIF‐1β knockout mice. We demonstrated previously that upregulation of several genes in hepatocytes during hypoxia requires autocrine release and activation of transforming growth factor‐1 (TGF‐β1). To determine if TGF‐β1 is required for the upregulation of SDF‐1 during hypoxia, primary mouse hepatocytes were pretreated with a TGF‐β1 receptor antagonist (SB‐431542) and placed in hypoxic conditions for 72 hrs. Pretreatment with SB‐431542 completely inhibited upregulation of SDF‐1 by hypoxia, suggesting TGF‐β is required for upregulation of SDF‐1 in hypoxic hepatocytes. Additionally, while treatment of hepatocytes with TGF‐β1 upregulated SDF‐1, this effect did not require HIF‐1α, suggesting that TGF‐β1 is downstream of HIF‐1α activation. We previously demonstrated that hypoxia upregulates thrombospondin‐1 in hepatocytes, which could be responsible for activation of latent TGF‐β1. Upregulation of SDF‐1 by hypoxia, however was not different between hepatocytes isolated from wild‐type or thrombospondin‐1 knockout mice. The results indicate that hypoxia activates HIF‐1α in hepatocytes, which leads to activation of latent‐TGF‐β1. TGF‐β1 then acts in an autocrine fashion to upregulate SDF‐1. However, the mediator responsible for converting latent TGF‐β to its active form remains unknown.Support or Funding InformationNIH grant 2 R01 DK073566NIH Training Grant T32 ES007255This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.