A Gut-Restricted Liver X Receptor Agonist Ameliorates Liver Injury in Experimental Short Bowel Syndrome.

Abstract

BACKGROUND & AIMS: Short bowel syndrome (SBS) arises from the surgical removal of extensive portions of the small intestine and is associated with high morbidity, including intestinal failure-associated liver disease (IFALD). Earlier studies revealed that orally administered systemic liver X receptor (LXR) agonist suppresses IFALD in mice and implicated intestinally derived high-density lipoprotein (HDL) in liver protection. Here we aimed to move away from the use of systemic LXR agonists because they have failed in clinical trials due to hepatic steatosis and hyperlipidemia, to determine if a gut-restricted LXR agonist could provide hepatoprotection in SBS. METHODS: We synthesized and characterized WUSTL0717, an amide analog of GW3965, as a putative gut-restricted LXR agonist, and evaluated its potential to improve the outcomes in a preclinical mouse model of SBS. RESULTS: WUSTL0717 exhibited exceptional intestinal retention in pharmacokinetic analyses and activated LXR target genes in the small intestine but not the liver. Whereas small bowel resection lowered many lipid metabolites in portal venous plasma, WUSTL0717 treatment increased portal venous Apolipoprotein A1 (ApoA1), the core protein of HDL, and spared portal venous phospholipids known to be enriched on HDL. Accordingly, intestinal ApoA1 deficiency exacerbated IFALD, and in wild-type mice, portal venous ApoA1 and phospholipids inversely correlated with hepatic collagen accumulation. In addition, WUSTL0717 improved nutrient absorption and promoted body weight restoration in SBS. CONCLUSIONS: These data underscore the potential of gut-restricted LXR agonists to preserve metabolic health in the context of SBS. By acting locally in the intestine, WUSTL0717 positively mitigates profibrotic liver injury while avoiding systemic availability.