Maternal obesity and consumption of a high-fat diet significantly elevate risk for pediatric
nonalcoholic fatty liver disease (
NAFLD), affecting 10% of children in the US. Almost half of these children are diagnosed with
nonalcoholic steatohepatitis (NASH), a leading etiology for
liver transplant. Animal models show that signs of liver injury and perturbed lipid metabolism associated with
NAFLD begin in utero; however, safe dietary
therapeutics to blunt developmental programming of
NAFLD are unavailable. Using a mouse model of maternal Western-style diet (WD), we previously showed that
pyrroloquinoline quinone (PQQ), a potent dietary
antioxidant, protected offspring of WD-fed dams from development of
NAFLD and NASH. Here, we used untargeted mass spectrometry-based lipidomics to delineate lipotoxic effects of WD on offspring liver and identify
lipid targets of PQQ. PQQ exposure during pregnancy altered hepatic
lipid profiles of WD-exposed offspring, upregulating
peroxisome proliferator-activated receptor (
PPAR) α signaling and mitochondrial
fatty acid oxidation to markedly attenuate
triglyceride accumulation beginning in utero. Surprisingly, the abundance of very long-chain
ceramides, important in promoting gut barrier and hepatic function, was significantly elevated in PQQ-treated offspring. PQQ exposure reduced the hepatic
phosphatidylcholine/
phosphatidylethanolamine (PC/PE) ratio in WD-fed offspring and improved
glucose tolerance. Notably, levels of protective n - 3
polyunsaturated fatty acids (PUFAs) were elevated in offspring exposed to PQQ, beginning in utero, and the increase in n - 3 PUFAs persisted into adulthood. Our findings suggest that PQQ supplementation during gestation and lactation augments pathways involved in the biosynthesis of long-chain
fatty acids and plays a unique role in modifying specific bioactive
lipid species critical for protection against
NAFLD risk in later life.