Early-Life Vitamin A Deficiency Induces Tissue-Specific Oxylipin Remodeling and Hepatic Inflammation.

Background: Retinoid signaling is implicated in regulating membrane-bound polyunsaturated fatty acids (PUFAs), which serve as substrates for oxylipin biosynthesis. Dysregulated vitamin A status and altered oxylipin profiles have both been associated with the development of metabolic diseases. However, whether early-life vitamin A deficiency (VAD) causally influences oxylipin metabolism and liver health remains unclear. Methods: C57BL/6J mouse pups were exposed to either a vitamin A-deficient (VD) or vitamin A-replete (VR) AIN-93G-based diet during the fetal and suckling periods, and they weremaintained on the same diet from weaning (3 weeks of age) to 9 weeks of age. Oxylipin composition in plasma, liver and cerebral tissues was analyzed by liquid chromatography-mass spectrometry. Hepatic and cerebral expressions of genes involved in inflammation, phospholipid and PUFA catabolism, and oxylipin synthesis were analyzed using RT-qPCR. Results: Dietary deprivation induced severe VAD, which significantly altered 21 oxylipins in the liver and 34 oxylipins in the cerebrum, but did not affect the plasma oxylipin profile. In the liver, all altered oxylipins were elevated by VAD, the majority being ω-6-derived species with pro-inflammatory properties. In contrast, 27 altered oxylipins were lower in the VD cerebrum, including more ω-3-derived species. Multivariate analysis identified 11,12-EpETrE, 8,9-EpETrE, and 20-HETE as key hepatic oxylipins distinguishing VAD. VAD also altered hepatic expression of genes involved in membrane phospholipid remodeling (PNPLA8, PLA2G6, LPCAT3), and oxylipin metabolism (ALOX5, EPHX2), and it upregulated inflammatory signaling in the liver only, while fibrosis markers (TGFB1, COL1A1) remained unchanged. Conclusions: These findings demonstrate that early-life VAD is associated with tissue-specific alterations in oxylipin metabolism and hepatic inflammatory responses.