Beta-hydroxybutyrate and niacin protect the murine liver from acute inflammatory injury via activation of the Gpr109 receptor
Introduction: Inflammation is an important component of many forms of acute liver injury. Beta-hydroxybutyrate (BHB) and niacin are ligands for the plasma membrane receptor GPR109 which is expressed on Kupffer cells (KC). Some GPRs have immunomodulatory actions but a role for GPR109 in hepatic inflammation has not been investigated. Aim: Assess the role of GPR109 as a regulator of inflammation in acute liver injury, and the potential for therapy by its ligands BHB or niacin. Methods: WT (C57BL/6), Gpr109 null, and WT siRNA Gpr109 treated male mice were subject to LPS/d-Gal induced acute liver injury with/without sodium BHB or niacin (one i.p. dose 380 mcg and 30 mcg per g body weight respectively). WT mice were subject to APAP induced liver injury +/− saline, BHB, or niacin (two i.p. doses). Plasma ALT, H&E, neutrophil staining, liver inflammatory gene transcripts, and mortality were quantified. Inflammatory peritoneal macrophages and KC were isolated from WT and Gpr109 null mice and activated with LPS and ATP, +/− BHB or niacin. Pro-inflammatory gene transcripts, and IL1β release was quantified. NF-KB GFP reporter transgenic mice were treated with LPS and BHB or saline, livers isolated, and GFP expression quantified in KC. Results: Gpr109 null and Gpr109 siRNA treated WT mice had lethality from LPS/D-gal (5/7 and 6/6, respectively). No deaths in WT control, scramble siRNA treated animals (0/10 and 0/6, respectively). BHB or niacin versus saline supplementation protected WT mice from LPS/D-gal and APAP induced acute liver injury with reduced ALT (1010 +/− 905 and 1090 +/−1069 versus 8806 +/−1600 IU/L in APAP model P<0.05) and liver neutrophil infiltration (11.4 +/− 2.3 and 22.5 +/−5.8 versus 76.5 +/− 8.9 cells per 40 × magnified high power field P<0.05 in APAP model), as well as hepatic expression of nlrp3, casp1, and pro-il1 β. BHB did not protect Gpr109 null or Gpr109 siRNA treated mice. In macrophages, BHB and niacin dose dependently decreased LPS induced intracellular Pro- IL1β and IL1β release in a GPR109 dependent manner. BHB or niacin suppressed LPS mediated pro-inflammatory gene transcription in KC in vitro and in vivo in NF-KB GFP reporter mice. Conclusions: BHB and niacin have potent anti-inflammatory effects via the GPR109 plasma membrane receptor on Kupffer cells. This pathway is endogenously active, and can be additionally stimulated to provide hepatoprotection in a numbers of forms of liver disease.
Hoque, R; Farooq, A; Gorelick, F; Mehal, W
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