Glucose is an essential energy source but excessive glucose causes diseases and accelerates aging in many species. We previously reported that a glucose-rich diet shortens the lifespan of C. elegans via accumulating saturated fatty acids (SFAs) and toxic metabolites (Lee et al., 2015, Genes Dev.). However, underlying mechanisms by which high-glucose diets shorten lifespan by affecting lipid metabolism remain incompletely understood. Here, we find that LPIN-1/Lipin 1, a phosphatidic acid phosphatase and a potential transcriptional coregulator, prevents worms from the lifespan-shortening effects of high-glucose diets. Through performing RNA-sequencing analysis, we showed that the transcriptomic changes caused by
lpin-1 RNAi were partially reversed by glucose-rich diet feeding. Consistent with a previous report showing that LPIN-1 is a negative regulator of SBP-1/sterol regulatory element-binding protein (SREBP), a key transcription factor for fat synthesis (Smulan et al., 2016, Cell Rep.), we found that
lpin-1 RNAi upregulated fat-metabolic SBP-1 target genes. In contrast, we showed that overall transcriptomic changes caused by
lpin-1 RNAi positively correlated with those by RNAi targeting
sbp-1 or
mdt-15/mediator 15, a transcriptional coregulator of SBP-1. We also found that
lpin-1 RNAi reduced lipid levels in glucose-rich diets, leading to compensatory activation of SBP-1. Specifically, we showed that
lpin-1 RNAi upregulated lipid synthesis/desaturation genes and downregulated lipolysis genes in glucose and lipid metabolic pathways. Overall, these data suggest that LPIN-1 maintains lipid homeostasis under glucose-rich diets by altering lipid levels and composition in worms. Consistently, we found that
lpin-1 RNAi reversed the composition of fatty acids altered by glucose-rich diet feeding; the levels of SFAs and monounsaturated fatty acids (MUFAs) were decreased by
lpin-1 RNAi but were increased by glucose-rich diets. In contrast, the levels of two omega-6 polyunsaturated fatty acids (PUFAs), linoleic acid (18:2n-6) and arachidonic acid (20:4n-6), were increased by
lpin-1 RNAi but decreased by glucose-rich diet feeding. Importantly, supplementation with linoleic acid or arachidonic acid suppressed the shortened lifespan of
lpin-1(RNAi) worms under glucose-rich conditions. Thus, proper metabolic flow from glucose to omega-6 PUFAs via LPIN-1 is crucial for maintaining health and normal lifespan against dietary glucose toxicity in animals.