1. Academic Validation
  2. Farnesoid X Receptor Activation Protects Liver From Ischemia/Reperfusion Injury by Up-Regulating Small Heterodimer Partner in Kupffer Cells

Farnesoid X Receptor Activation Protects Liver From Ischemia/Reperfusion Injury by Up-Regulating Small Heterodimer Partner in Kupffer Cells

  • Hepatol Commun. 2020 Feb 13;4(4):540-554. doi: 10.1002/hep4.1478.
Dan Jin 1 2 Tianfei Lu 3 Ming Ni 1 Han Wang 1 Jiang Zhang 3 Chenpeng Zhong 3 Chuan Shen 3 Jun Hao 3 Ronald W Busuttil 1 Jerzy W Kupiec-Weglinski 1 Jianjun Zhang 3 Ning Xu 3 Yuan Zhai 1
Affiliations

Affiliations

  • 1 Department of Surgery David Geffen School of Medicine University of California Los Angles Los Angeles CA.
  • 2 Department of Obstetrics and Gynecology and Shanghai Key Laboratory of Gynecologic Oncology Renji Hospital School of Medicine Shanghai Jiaotong University Shanghai China.
  • 3 Department of Hepatic Surgery and Liver Transplantation Center Renji Hospital School of Medicine Shanghai Jiaotong University Shanghai China.
Abstract

Farnesoid X receptor (FXR) is the nuclear receptor of bile acids and is involved in innate immune regulation. FXR agonists have been shown to protect multiple organs from inflammatory tissue injuries. Because liver expresses high levels of FXR, we explored the potential therapeutic benefits and underlying mechanisms of pharmacologic FXR activation in a murine model of partial liver warm ischemia. Pretreatment of mice with FXR Agonist 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064) attenuated liver ischemia/reperfusion injuries (IRIs) in wild-type but not FXR knockout mice. Posttreatment with GW4064 facilitated liver recovery from IRI. Mechanistically, Kupffer cells (KCs) expressed much higher levels of FXR than bone marrow-derived macrophages (BMMs). Pretreatment of KCs but not BMMs with GW4064 resulted in lower tumor necrosis factor α but higher interleukin-10 expressions following Toll-like Receptor stimulation. FXR-targeted gene small heterodimer partner (SHP) was critical for the regulation of KC response by GW4064. In vivo, the depletion of KCs but not cluster of differentiation (CD) 11b+ cells or knockdown of SHP diminished the immune regulatory effect of GW4064 in liver IRI. Thus, FXR activation protects liver from IRI by up-regulating SHP in KCs to inhibit the liver proinflammatory response.

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