Characterization of a gut-restricted LXR agonist and its utility in ameliorating liver injury in experimental short gut syndrome
Short bowel syndrome (SBS) results from the surgical removal of extensive portions of the small intestine and is associated with high morbidity, including intestinal failure-associated liver disease (IFALD). We aim to identify effective, targeted therapies to combat IFALD while promoting small intestinal remodeling that optimizes intestinal health and nutrient absorption. Following previous findings that an LXR agonist administered orally suppresses liver injury in a mouse model of SBS, we sought application of a gut-restricted LXR agonist to avoid potential for systemic activation of LXR. We synthesized and characterized WUSTL0717 as a potential gut-restricted hydrophobic derivative of the well-known LXR agonist GW3965and tested its ability to improve outcomes in a mouse model of SBS. Pharmacokinetic analysis in mice revealed overwhelming intestinal retention of WUSTL0717.  The  compound activated a panoply of LXR target genes, including Abca1, in the small intestine but not the liver. It also increased ileal transcript levels of Apoa1 that encodes the core protein of high-density lipoprotein (HDL) and raised HDL levels in plasma. WUSTL0717 was efficacious in protecting against IFALD. Additionally, WUSTL0717 improved nutrient absorption after small intestinal resection and promoted restoration of body weight. These data identify the LXR agonist WUSTL0717 as a gut-restricted drug that may provide therapeutic benefits for treating SBS-associated IFALD while avoiding unwanted effects of systemic LXR agonists. Overall design: The 8-week-old C57BL/6 male mice underwent either 50-60% small bowel resection or sham surgeries. Three weeks after the operation, the mice received daily treatments of WUSTL0717 (30 mg/kg) or vehicle for 7 weeks. They were then sacrificed, and the duodenum, ileum, and liver were collected and processed for RNA sequencing.