Polyunsaturated fatty acid desaturation is a mechanism for glycolytic NAD+ recycling
- Authors
- Kim, Wondong; Deik, Amy; Gonzalez, Clicerio; Gonzalez, Maria Elena; Fu, Feifei; Ferrari, Michele; Churchhouse, Claire L.; Florez, Jose C.; Jacobs, Suzanne B.R.; Clish, Clary B.; Rhee, Eugene P.
- Issue Date
- Apr-2019
- Publisher
- Cell Press
- Keywords
- delta-5-desaturase; delta-6-desaturase; FADS1-3; highly unsaturated fatty acids; NAD + recycling; polyunsaturated fatty acids; SLC16A11
- Citation
- Cell Metabolism, pp 856 - 870
- Pages
- 15
- Indexed
- SCI
SCIE
SCOPUS
- Journal Title
- Cell Metabolism
- Start Page
- 856
- End Page
- 870
- URI
- https://scholarworks.bwise.kr/erica/handle/2021.sw.erica/113960
- DOI
- 10.1016/j.cmet.2018.12.023
- ISSN
- 1550-4131
1932-7420
- Abstract
- The reactions catalyzed by the delta-5 and delta-6 desaturases (D5D/D6D), key enzymes responsible for highly unsaturated fatty acid (HUFA) synthesis, regenerate NAD + from NADH. Here, we show that D5D/D6D provide a mechanism for glycolytic NAD + recycling that permits ongoing glycolysis and cell viability when the cytosolic NAD + /NADH ratio is reduced, analogous to lactate fermentation. Although lesser in magnitude than lactate production, this desaturase-mediated NAD + recycling is acutely adaptive when aerobic respiration is impaired in vivo. Notably, inhibition of either HUFA synthesis or lactate fermentation increases the other, underscoring their interdependence. Consistent with this, a type 2 diabetes risk haplotype in SLC16A11 that reduces pyruvate transport (thus limiting lactate production) increases D5D/D6D activity in vitro and in humans, demonstrating a chronic effect of desaturase-mediated NAD + recycling. These findings highlight key biologic roles for D5D/D6D activity independent of their HUFA end products and expand the current paradigm of glycolytic NAD + regeneration. Kim et al. find that highly unsaturated fatty acid (HUFA) synthesis is a mechanism for glycolytic NAD + recycling, analogous to lactate fermentation. This finding highlights a key biologic role for lipid desaturation independent of HUFA end products and provides insight into genetic studies linking HUFA desaturation with human disease. © 2018 Elsevier Inc.
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