P4649 - Cholangiocyte Response to Seladelpar Treatment

Award: Presidential Poster Award

Xia Wu, PhD¹, Yen-Wen Chen, PhD², Jiangao Song, MS¹, Edward E Cable, PhD¹, Jeff D Johnson, ¹, Joanne Elliott, ², Francisco J Caballero-Camino, PhD³, Xin Chen, PhD¹, Yun-Jung Choi, PhD¹, Robert Martin, PhD¹, Jeffrey W Stebbins, PhD¹, Jesus M Banales, PhD³, Charles A. McWherter, PhD^1
1CymaBay, a Gilead Sciences Company, Fremont, CA; ²Triple Ring Technologies, Newark, CA; ³Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country, San Sebastian, Extremadura, Spain

Introduction: Cholangiocytes are epithelial cells that line bile ducts and play a central role as the site of injury in primary biliary cholangitis (PBC). The Phase 3 RESPONSE trial in patients with PBC demonstrated that seladelpar, a selective peroxisome proliferator–activated receptor-delta (PPAR𝛿) agonist, reduced bile acid pools, improved cholestatic and liver injury markers (alkaline phosphatase, gamma-glutamyl transpeptidase, and alanine aminotransferase), and decreased the pruritogenic cytokine interleukin (IL)-31, with accompanying improvement in patient-reported pruritus. Given the central role of cholangiocytes in PBC pathobiology, we examined the human cholangiocyte H69 cellular response to seladelpar treatment as a potential translational model for its observed clinical profile.

Methods: H69 cells were cultured in vitro and exposed to seladelpar at a range of concentrations and times. Inflammatory mediators, including IL-17, a known mediator in cholangiopathy, were used in addition to seladelpar. Gene expression changes were analyzed by bulk RNAseq and quantitative polymerase chain reaction assays. Secreted cytokines in culture media were analyzed with Meso Scale Discovery (MSD) assays.

Results: Treatment of H69 cells with 10µM seladelpar induced robust gene expression changes. Notably, seladelpar significantly upregulated several genes important in lipid pathways, including those involved in fatty acid β-oxidation: ANGPTL4, CPT1A, ACADVL, HADHA, HADHB, ACAA2, and ECH1. After 22 hours of seladelpar treatment with concentrations as low as 10nM, the gene expression of PPAR𝛿-activated genes, PDK4 and ANGPTL4, increased by 4- and 8-fold, respectively. IL-17 treatment induced an inflammatory response in H69 cells, including upregulation of CXCL10, CCL5, CXCL8, CXCL1, and IL-6. MSD assays confirmed IL-17-induced secretion of the cytokines IL-6, IL-8, IL-1β, and Tumor Necrosis Factor-α by H69 cells; cotreatment of H69 cells with seladelpar and IL-17 attenuated this IL-17–induced response. Interferon (IFN)-β-, IFN-λ-, and IFN-stimulated genes (IFIT1, ISG15, RSAD2, CXCL10); chemokine genes (CCL5, CXCL1, CCL20); and human leukocyte antigen (HLA) genes (HLA-F, HLA-E and HLA-DPB1) were reduced in the seladelpar- and IL-17–cotreated H69 cells compared with IL-17 alone.

Discussion: This is the first report of the effects of selective PPAR𝛿 activation in a human cholangiocyte cell line. These initial results suggest seladelpar modulated multiple inflammatory mediators that need further study.


Disclosures:


Xia Wu, PhD¹, Yen-Wen Chen, PhD², Jiangao Song, MS¹, Edward E Cable, PhD¹, Jeff D Johnson, ¹, Joanne Elliott, ², Francisco J Caballero-Camino, PhD³, Xin Chen, PhD¹, Yun-Jung Choi, PhD¹, Robert Martin, PhD¹, Jeffrey W Stebbins, PhD¹, Jesus M Banales, PhD³, Charles A. McWherter, PhD¹. P4649 - Cholangiocyte Response to Seladelpar Treatment, ACG 2024 Annual Scientific Meeting Abstracts. Philadelphia, PA: American College of Gastroenterology.