Hepatic ELOVL2 regulates sex differences in mouse heart omega-3 polyunsaturated fatty acid metabolism

Premenopausal females have higher docosahexaenoic acid (DHA, 22:6n-3) levels than males, with elongation of very long chain fatty acids-like 2 (Elovl2) implicated in regulating these differences. We employed a liver-specific Elovl2-KO model to determine how hepatic ELOVL2 activity influences sex differences in DHA synthesis and turnover rates in mice. LoxP flanked Elovl2:Alb-Cre^+/- or Elovl2:Alb-Cre^-/- C57BL/6J male and female pups (n=64 per sex) were allocated into one of four groups: 1) male liver Elovl2-KO, 2) female liver Elovl2-KO, 3) male control or 4) female control. Following 5-weeks low carbon-13 (δ¹³C)-eicosapentaenoic acid (EPA, 20:5n-3) feeding, mice were switched to high δ¹³C-EPA and blood/tissues collected up to 112 days post diet-switch to determine fatty acid levels and δ¹³C to support n-3 PUFA synthesis and turnover estimates. Following interaction effects (sex x genotype, p < 0.05), liver and serum DPAn-3 half-lives and plasma DPAn-3 turnover rates became longer in Elovl2-KO females compared to controls, but not males. Furthermore, heart DHA half-lives were longer in male Elovl2-KO only and heart DHA turnover sex differences in control were lost with Elovl2-KO. Genotype effects (p < 0.001) were observed for all tissue kinetic parameters of DPAn-3 and DHA. Gene expression revealed hepatic Fads1 was 64% higher (p<0.01) in females than males, while Fads2 was upregulated exclusively in female KO compared to female controls (71%, p<0.05). In conclusion, hepatic ELOVL2 regulates sex differences in n-3 PUFA metabolism in the liver and heart, with females demonstrating a potentially greater capacity to maintain DHA levels in the absence of ELOVL2.