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Pituitary Adenylate Cyclase-activating Polypeptides Prevent Hepatocyte Damage by Promoting Yes-associated Protein in Liver Ischemia-Reperfusion Injury

Liu, Yuan MD1,2; Lu, Tianfei MD1,2; Zhang, Cheng MD, PhD1,3; Xue, Zhengze MD1,3; Xu, Jin MD1,4; Busuttil, Ronald W. MD, PhD1; Xia, Qiang MD2; Xu, Ning MD2; Kupiec-Weglinski, Jerzy W. MD, PhD1; Ji, Haofeng MD1

doi: 10.1097/TP.0000000000002742
Original Basic Science—Liver
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Background. Hepatic ischemia-reperfusion injury (IRI) is a severe complication in liver transplantation, hepatectomy, and hemorrhagic shock. As neuropeptides transmit the regulatory signal between nervous and immune systems communication, our previous study documented that pituitary adenylate cyclase-activating polypeptides (PACAP) depressed hepatic Toll-like receptor 4 immune response in liver IRI.

Methods. Here, we focused on how PACAP suppressed hepatocellular damage and enhanced hepatocyte regeneration in a murine model of partial liver warm IRI.

Results. Yes-associated protein (YAP), a cellular modulator of tissue regeneration, was readily induced in wild type (WT) mouse IR-livers. As its induction was failed in PACAP-deficient livers, PACAP supplement enhanced YAP expression in WT mouse and promoted its nuclear translocation and downstream antioxidative/regenerative genes expression both in vivo and in vitro. Further, verteporfin, a YAP transcriptional inhibitor, abolished PACAP-mediated hepatoprotection significantly. Meanwhile, blockade of protein kinase A (PKA)–CRE-binding protein (CREB) signaling recreated liver damage in PACAP-protected liver as well as impeded stimulation on YAP and its downstream gene expressions. Consistently, inhibition of PKA-CREB decreased PACAP-promoted YAP expression in primary hepatocytes culture, and made them vulnerable to H2O2 stress in vitro. In addition, lysophosphatidic acid, another Hippo pathway inhibitor, failed to affect PACAP-mediated hepatoprotection or hepatocellular YAP induction. This implies that PACAP regulated YAP through PKA-CREB pathway at the transcriptional level rather than canonical hippo pathway.

Conclusions. Our study discovered the neural modulation of PACAP-YAP axis in hepatic cytoprotection and homeostasis in liver IRI. These reveal a novel insight of neuropeptide PACAP in combating liver IRI in clinical patients.

1 Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, CA.

2 Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

3 Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.

4 Department of Pancreatic Surgery, Shengjing Hospital, China Medical University, Shenyang, China.

Received 31 January 2019. Revision received 10 March 2019.

Accepted 15 March 2019.

This work was supported by grants from NIH R21 AI122155 and AI138165 (H.J.), NIH PO1 AI120944, RO1 DK107533, DK102110, and DK062357 (J.W.K.W.), and The Dumont Research Foundation.

The authors declare that they have no conflict of interest.

Y.L. participated in the performance of the research, data analysis and article draft. T.L. and C.Z. participated in the performance of the research and data analysis. Z.X. and J.X. participated in the performance of the research. R.W.B. and J.W.K.W. participated in article revision. Q.X., N.X., and H.J. participated in the research design, discussion, and article writing. Y.L., T.L., and C.Z. contributed equally to this work.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Haofeng Ji, MD, Dumont-UCLA Transplant Center, 77–120 CHS, 10833 Le Conte Ave, Los Angeles, CA 90095. (hji@mednet.ucla.edu).

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