Monocyte Chemoattractant Protein-Induced Protein 1 Targets Hypoxia-Inducible Factor 1α to Protect Against Hepatic Ischemia/Reperfusion Injury.

Abstract

Sterile inflammation is an essential factor causing hepatic ischemia/reperfusion (I/R) injury. As a critical regulator of inflammation, the role of monocyte chemoattractant protein-induced protein 1 (MCPIP1) in hepatic I/R injury remains undetermined. In this study, we discovered that MCPIP1 downregulation was associated with hepatic I/R injury in liver transplant patients and a mouse model. Hepatocyte-specific Mcpip1 gene knockout and transgenic mice demonstrated that MCPIP1 functions to ameliorate liver damage, reduce inflammation, prevent cell death, and promote regeneration. A mechanistic study revealed that MCPIP1 interacted with and maintained hypoxia-inducible factor 1α (HIF-1α) expression by deubiquitinating HIF-1α. Notably, the HIF-1α inhibitor reversed the protective effect of MCPIP1, whereas the HIF-1α activator compensated for the detrimental effect of MCPIP1 deficiency. Thus, we identified the MCPIP1-HIF-1α axis as a critical pathway that may be a good target for intervention in hepatic I/R injury. (Hepatology 2018; 00:000-000).

• Authors: Peng Sun, Yue-Xin Lu, Daqing Cheng, Kuo Zhang, Jilin Zheng, Yupeng Liu, Xiaozhan Wang, Yu-Feng Yuan, Yi-Da Tang
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 68 Issue 6 Pg. 2359-2375 (12 2018) ISSN: 1527-3350 [Electronic] United States
• PMID: 29742804 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 by the American Association for the Study of Liver Diseases.

Chemical References

• Hypoxia-Inducible Factor 1, alpha Subunit
• Transcription Factors
• Ribonucleases
• ZC3H12A protein, human
• Zc3h12a protein, mouse

Topics

• Animals
• Apoptosis
• Case-Control Studies
• Hepatocytes (physiology)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Liver (pathology)
• Liver Diseases (metabolism, pathology)
• Liver Regeneration
• Male
• Mice
• Primary Cell Culture
• Reperfusion Injury (metabolism)
• Ribonucleases (metabolism)
• Transcription Factors (metabolism)