LRH-1 agonist DLPC through STAT6 promotes macrophage polarization and prevents parenteral nutrition associated cholestasis in mice

Background & Aims: Parenteral nutrition associated cholestasis (PNAC) is important complication in patients with intestinal failure with reduced LRH-1 expression. Here, we hypothesized that LRH-1 activation by its agonist, dilauroylphosphatidylcholine (DLPC), would trigger STAT6 signaling and hepatic macrophage polarization that would mediate hepatic protection in PNAC. Approach & Results: PNAC mouse model (oral DSSx4d followed by PNx14d; DSS-PN) was treated with LRH-1 agonist DLPC (30 mg/kg/day) intravenously. DLPC treatment prevented liver injury and cholestasis while inducing hepatic mRNA expression of Nr5a2), Abcb11, Abcg5, Abcg8, Nr0b2 and Abcc2 mRNA, all of which were reduced in PNAC mice. To determine the mechanism of DLPC effect, we performed RNA-sequencing analysis of liver from Chow, DSS-PN and DSS-PN/DLPC mice, which revealed DLPC upregulation of the anti-inflammatory STAT6 pathway. In intrahepatic mononuclear cells from PNAC mice, DLPC treatment prevented upregulation of pro-inflammatory (M1) genes, suppressed activation of NFκB and induced phosphorylation of STAT6 and its target genes, indicating M2 macrophage polarization. In vitro incubation of DLPC with cultured macrophages showed that the increased Il-1b and Tnf induced by exposure to LPS or phytosterols was reduced significantly, which was associated with increased STAT6 binding to promoters of its target genes. Suppression of STAT6 expression by siRNA in THP-1 cells exposed to LPS, phytosterols or both resulted in enhanced elevation of IL-1B mRNA expression. Furthermore, protective effect of DLPC in THP-1 cells was abrogated by STAT6 siRNA. Conclusions: These results indicate that activation of LRH-1 by DLPC may protect from PNAC liver injury through STAT6-mediated macrophage polarization. Export