Generation of high density lipoprotein (HDL) requires apoA1 and the cholesterol transporter ABCA1. Although the liver generates most HDL in blood, small intestines also can synthesize HDL. However, distinct functions for intestinal HDL are unknown. Here we designed intestine-specific activation of LXR via low-dose administration of GW3965, LXR agonist. The liver status was improved by therapeutics that elevated and depended upon intestinal HDL production via GW3965. Thus, protection of the liver from injury in response to gut-derived signals like LPS is a major function of intestinally synthesized HDL. Overall design: GW3965 (Sigma-Aldrich) was suspended in 0.5% carboxymethyl cellulose and was orally administered twice weekly at 1 mg/kg/day for the last 5 weeks in the 10-week period following intestinal resection (small bowel resection; SBR) to floxed control and intestine-specific knockout of ABCA1. The liver and ileum tissue was isolated and RNA was isolated by RNeasy Mini Kit (Qiagen). The isolated RNA samples were sequenced on an Illumina NovaSeq-6000 using paired end reads extending 150 bases.