Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid (EPA) elongation. This study demonstrates that dietary DHA reduces its own synthesis in the liver by inhibiting the elongation of EPA, a key step in DHA production. Using compound-specific isotope analysis (CSIA), the researchers found that when dietary DHA is low, the brain receives DHA synthesized from alpha-linolenic acid (ALA). Dietary DHA increases mouse liver and serum EPA levels, which is dependent on ALA. However, the source of increased EPA is slowed EPA metabolism, not increased DHA retroconversion. DHA feeding alone or with ALA lowers liver elongation of very long chain (ELOVL2, EPA elongation) enzyme activity. A liver-specific Elovl2 knockout mouse study confirmed that DHA feeding in the presence or absence of functional liver ELOVL2 yields similar results. An enzyme competition assay showed that DHA inhibits EPA elongation through both uncompetitive and noncompetitive mechanisms. In humans, DHA supplementation increases EPA levels, which is dependent on a SNP (rs953413) in the ELOVL2 gene. The study concludes that dietary DHA downregulates its liver synthesis by inhibiting EPA elongation, identifying a novel feedback inhibition pathway.Dietary docosahexaenoic acid (DHA) downregulates liver DHA synthesis by inhibiting eicosapentaenoic acid (EPA) elongation. This study demonstrates that dietary DHA reduces its own synthesis in the liver by inhibiting the elongation of EPA, a key step in DHA production. Using compound-specific isotope analysis (CSIA), the researchers found that when dietary DHA is low, the brain receives DHA synthesized from alpha-linolenic acid (ALA). Dietary DHA increases mouse liver and serum EPA levels, which is dependent on ALA. However, the source of increased EPA is slowed EPA metabolism, not increased DHA retroconversion. DHA feeding alone or with ALA lowers liver elongation of very long chain (ELOVL2, EPA elongation) enzyme activity. A liver-specific Elovl2 knockout mouse study confirmed that DHA feeding in the presence or absence of functional liver ELOVL2 yields similar results. An enzyme competition assay showed that DHA inhibits EPA elongation through both uncompetitive and noncompetitive mechanisms. In humans, DHA supplementation increases EPA levels, which is dependent on a SNP (rs953413) in the ELOVL2 gene. The study concludes that dietary DHA downregulates its liver synthesis by inhibiting EPA elongation, identifying a novel feedback inhibition pathway.