1173-P: Maternally Supplemented PQQ Targets Ceramide Metabolism in Offspring to Blunt Developmental Programming of NAFLD

Abstract

Maternal obesity is a key risk factor for pediatric nonalcoholic fatty liver disease (NAFLD). Using a mouse model of Western-style diet (WD)-induced maternal obesity, we studied effects of supplementing dams with pyrroloquinoline quinone (PQQ; a potent dietary antioxidant) during gestation and lactation on hepatic lipid metabolism and fibrosis in offspring at postnatal day (PND) 14 and at 16 wks after a 4 wk WD challenge. Maternal PQQ (mWDPQQ) decreased neonatal hepatic triglycerides (30%, P=0.0012) and altered bioactive sphingolipids in adult offspring compared with those exposed to maternal WD (mWD), with no change in weight gain. mWDPQQ increased very long chain ceramides (VLCer; 219%, P=0.0002), associated with protection from fibrosis, concomitant with decreased expression of genes promoting ceramide degradation (Asah2, P=0.0014 and Acer3, P=0.02). Expression of Scd1, a desaturase regulating triglyceride biosynthesis, was attenuated in mWDPQQ offspring at PND14 (P=0.0009) and at 16 wks (P=0.0012), while expression of Elovl3, an enzyme promoting elongation of saturated fatty acids and ceramide production, was increased (P=0.0026). Comparative pathway analysis of RNASeq data showed enrichment of pathways in fatty acid metabolism, hepatic fibrosis and, unexpectedly, signaling through the aryl hydrocarbon receptor (AHR; a ligand-activated transcription factor regulating immune function and hepatoxicity). Chromatin IP in mWDPQQ liver showed increased AHR binding to the Cyp1a1 promoter, its canonical target, as compared with mWD, suggesting AHR signaling may be activated by mWDPQQ. AHR binding to the Scd1 promoter, a known AHR target, was increased, as was binding to Asah2 and Acer3, putative new AHR targets regulating long-chain ceramide degradation. These findings suggest that maternal PQQ has both short and long-term effects on blunting steatosis/fibrosis and promoting VLCer increase through novel AHR targets, protecting offspring from NAFLD. Disclosure A.Mandala: None. A.M.Teague: None. R.Janssen: None. N.Patil: None. A.D.Joshi: None. J.E.Friedman: None. K.R.Jonscher: None. Funding National Institutes of Health (1R01DK121951)