Published online Jan 14, 2027. doi: 10.3748/wjg.125044
Revised: July 30, 2026
Accepted: September 29, 2026
Published online: January 14, 2027
Processing time: 131 Days and 14.4 Hours
Chronic inflammatory cholangiopathies involve bile duct injury, biochemical cholestasis, hepatocellular injury, immune cell recruitment, oxidative stress, and fibrogenic remodeling. We previously demonstrated that 20% dietary lauric acid (LA) protected against early 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced cholangiopathy (proof of concept) by activating liver receptor homolog-1 (LRH-1).
To determine whether concurrent low-dose 5% dietary LA supplementation attenuates 14-day DDC-induced cholangiopathy and to characterize the associ
Eight-week-old male C57BL/6J mice were fed for 14 days with either Chow, 0.1% DDC, 5% LA, or a 0.1% DDC diet supplemented with 5% LA.
DDC feeding induced severe hepatocellular and cholestatic liver injury, macrophage infiltration, ductular reaction, oxidative stress, hepatocyte senescence, and fibrogenic remodeling. LA supplementation significantly reduced DDC-induced elevations of serum aminotransferases, bilirubin, and total bile acids, and decreased hepatic F4/80-positive macrophage infiltration and Picrosirius red collagen staining. LA supplementation restored hepatic expression of LRH-1-dependent genes involved in bile acid homeostasis, which DDC suppressed. Furthermore, DDC suppressed ileal farnesoid X receptor-fibroblast growth factor 15 signaling, which LA normalized, and LA attenuated DDC-induced hepatic oxidative and nitrosative stress and improved the expression of mitochondrial fatty acid metabolism genes. LA was associated with suppressed hepatic fibrosis markers and promoted anti-inflammatory macrophage genetic signatures. Notably, DDC activated nuclear factor-kappa B binding to the C-C motif chemokine ligand 2 promoter and repressed LRH-1 transcription, which were reversed by LA supplementation.
Dietary LA attenuated chronic DDC cholangiopathy which was associated with reduced nuclear factor-kappa B-dependent inflammatory signaling and restoring LRH-1-mediated bile acid homeostasis. This positions LA as a potential therapeutic strategy for inflammatory cholangiopathy.
Core Tip: Lauric acid (LA), a dietary medium-chain fatty acid, was studied in a 14-day 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced mouse model. Concurrent 5% LA supplementation attenuated biochemical cholestasis, hepatocellular injury, ductular reaction, collagen deposition, oxidative stress, senescence, and cell-death markers. These effects were associated with reduced nuclear factor-kappa B - C-C motif chemokine ligand 2 signaling, restored liver receptor homolog-1-regulated gene expression, and increased hepatic dilauroylphosphatidylcholine abundance. This study demonstrates a decrease in the development of liver injury but was not designed to demonstrate reversal of established liver injury. Further investigation will be needed to determine if liver receptor homolog-1 or dilauroylphosphatidylcholine is required for LA protection in this model.