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Polyunsaturated Fatty Acid Desaturase‐Mediated NAD+ Recycling Permits Ongoing Glycolysis and Cell Proliferation

The delta‐5 desaturase (D5D) and delta‐6 desaturase (D6D), encoded by FADS1 and FADS2 respectively, are required for the synthesis of highly unsaturated fatty acids (HUFAs). Genetic variants associated with FADS1 and FADS2 expression are associated with HUFA content in circulating lipids, as well as fasting glucose, height and weight, and risk of colon and laryngeal cancer. Why genetic variation in HUFA synthesis has such a broad impact on human metabolic and proliferative phenotypes is unknown. Here, we show that HUFA synthesis is a mechanism for cytosolic NAD+ recycling that permits ongoing glycolysis. Consistent with this, lowering the cytosolic NAD+/NADH ratio via inhibition of mitochondrial respiration increased D5D and D6D activity in vitro and in vivo. Conversely, increasing the cytosolic NAD+/NADH ratio via expression of an NADH oxidase or activation of lactate dehydrogenase decreased D5D and D6D activity. Increasing D5D and D6D expression increased cytosolic NAD+/NADH, whereas reduced expression or inhibition of D5D and D6D decreased cytosolic NAD+/NADH and increased lactate production. Inhibition of D5D and D6D also reduced cell proliferation, an effect that was reversed by boosting cytosolic NAD+ but not with HUFA end‐product supplementation. Finally, we show that the type 2 diabetes risk haplotype in SLC16A11, which reduces pyruvate transport, also increases D5D and D6D activity, demonstrating the relevance of our findings to human disease. These results outline a novel link between glycolysis and HUFA desaturation mediated by cytosolic NAD+, and provide new insight on how D5D and D6D activity may impact glycemic, growth, and cancer traits in humans.