*Purpose: Farnesoid X receptor (FXR) is the major nuclear receptor of bile acids, which is also involved in the regulation of innate immune responses. As livers express high levels of FXR, we explored the potential therapeutic benefits and underlying mechanisms of pharmacological FXR activation in liver ischemia and reperfusion injury.

*Methods: In a murine liver partial warm ischemia model (60m and 90m), we treated mice with FXR agonist 3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064) or obeticholic acid (OCA) either 1h prior to the onset of ischemia (pretreatment, 1 dose) or starting at 24h post reperfusion (posttreatment 1 dose/day x3) to determine its effect on the activation or the resolution of liver IRI, respectively.

*Results: Pretreatment of mice with FXR agonists attenuated liver IRI and inhibited pro-inflammatory response in wild-type but not FXR knockout mice at 6h post reperfusion: the serum ALT levels and liver pro-inflammatory gene expressions were decreased with better preserved liver architectures (lower Suzuki scores in H/E staining). Posttreatment with GW4064 facilitated liver recovery from IRI (hepatocellular damages were fully repaired at day 5 vs. day 7 in controls) by inhibiting inflammatory and enhancing reparative gene (MerTK, TIM-4) expressions. Mechanistically, Kupffer cells (KCs), rather than bone marrow-derived macrophages (BMMs), expressed functional FXR. Pretreatment of KCs, but not BMMs, with GW4064 resulted in lower tumor necrosis factor-α but higher interleukin-10 productions upon toll-like receptor stimulation. FXR-targeted gene small heterodimer partner (SHP) was critical for the regulation of KC response by GW4064. as its knockdown by its specific siRNA diminished the immune regulatory effect of FXR activation. In vivo, the depletion of KCs (by clodronate encapsulated liposomes), but not infiltrating macrophages (CD11b⁺ by diphtheria toxin in CD11b-DTR mice), or knockdown of SHP (i.v. injection of its siRNA carried by mannose-conjugated polymers) abrogated the immune regulatory and cytoprotective effect of GW4064 in liver IRI.

*Conclusions: Phamacological activation of FXR protects livers from IRI by up-regulating SHP in KCs to inhibit liver proinflammatory response.

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