Caspase recruitment domain 6 protects against hepatic ischemia/reperfusion injury by suppressing ASK1
Author(s): ,
Hongliang Li
Affiliations:
Institute of Model Animals of Wuhan University, Wuhan 430060, China
Corresponding authors. Addresses: 16 Luo-Jia-Shan Road, Wuhan 430072, China; Tel/fax: +86 27 68756660 (Z. Huang), or 185 Donghu Road, Wuhan 430071, China; Tel/fax: +86 27 68759302 (H. Li).
,
Zan Huang
Affiliations:
College of Life Sciences, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan 430072, China
Corresponding authors. Addresses: 16 Luo-Jia-Shan Road, Wuhan 430072, China; Tel/fax: +86 27 68756660 (Z. Huang), or 185 Donghu Road, Wuhan 430071, China; Tel/fax: +86 27 68759302 (H. Li).
,
Ling Yang
Affiliations:
Institute of Model Animals of Wuhan University, Wuhan 430060, China
,
Xue-Yong Zhu
Affiliations:
Institute of Model Animals of Wuhan University, Wuhan 430060, China
,
Song Tian
Affiliations:
Institute of Model Animals of Wuhan University, Wuhan 430060, China
,
Daqing Cheng
Affiliations:
Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
,
Peng Sun
Affiliations:
Department of General Surgery, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200336, China
,
Xiaozhan Wang
Affiliations:
Institute of Model Animals of Wuhan University, Wuhan 430060, China
,
Wenzhe Mao
Affiliations:
Institute of Model Animals of Wuhan University, Wuhan 430060, China
Juan-Juan Qin
Affiliations:
Institute of Model Animals of Wuhan University, Wuhan 430060, China
EASL LiverTree™. Li H. Nov 1, 2018; 234545
Hongliang Li
Hongliang Li
Contributions
Journal Abstract
References
Graphical abstract

Graphical abstract

CARD6 plays an important role in hepatic I/R injury. CARD6 requires its ability to interact with ASK1 to protect against hepatic I/R injury. The CARD6-ASK1-Jnk/p-38 regulatory axis is important for the pathogenesis of hepatic I/R injury.

Background & Aims

The hepatic injury caused by ischemia/reperfusion (I/R) insult is predominantly determined by the complex interplay of sterile inflammation and liver cell death. Caspase recruitment domain family member 6 (CARD6) was initially shown to play important roles in NF-κB activation. In our preliminary studies, CARD6 downregulation was closely related to hepatic I/R injury in liver transplantation patients and mouse models. Thus, we hypothesized that CARD6 protects against hepatic I/R injury and investigated the underlying molecular mechanisms.

Methods

A partial hepatic I/R operation was performed in hepatocyte-specific Card6 knockout mice (HKO), Card6 transgenic mice with CARD6 overexpression specifically in hepatocytes (HTG), and the corresponding control mice. Hepatic histology, serum aminotransferases, inflammatory cytokines/chemokines, cell death, and inflammatory signaling were examined to assess liver damage. The molecular mechanisms of CARD6 function were explored in vivo and in vitro.

Results

Liver injury was alleviated in Card6-HTG mice compared with control mice as shown by decreased cell death, lower serum aminotransferase levels, and reduced inflammation and infiltration, whereas Card6-HKO mice had the opposite phenotype. Mechanistically, phosphorylation of ASK1 and its downstream effectors JNK and p38 were increased in the livers of Card6-HKO mice but repressed in those of Card6-HTG mice. Furthermore, ASK1 knockdown normalized the effect of CARD6 deficiency on the activation of NF-κB, JNK and p38, while ASK1 overexpression abrogated the suppressive effect of CARD6. CARD6 was also shown to interact with ASK1. Mutant CARD6 that lacked the ability to interact with ASK1 could not inhibit ASK1 and failed to protect against hepatic I/R injury.

Conclusions

CARD6 is a novel protective factor against hepatic I/R injury that suppresses inflammation and liver cell death by inhibiting the ASK1 signaling pathway.

Lay summary

The protein CARD6 plays an important role during the process of liver blood flow restriction (ischemia) and restoration (reperfusion). By suppressing the activity of ASK1, CARD6 can protect against hepatocyte injury. Targeting CARD6 is a potential strategy for prevention and treatment of ischemia/reperfusion injury.

Keyword(s)
CARD6, Hepatic ischemia/reperfusion, ASK1
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