Long‐Chain Acyl‐CoA synthetase 6 deficiency reduces the omega‐3 fatty acid DHA in the brain and disrupts motor control

Abstract

Docosahexaenoic acid (DHA) is an omega‐3 fatty acid that is highly abundant in the brain and thought to confer neuroprotection against many diseases and disorders through its anti‐inflammatory and antioxidant actions, yet the fundamental mechanisms regulating the enrichment of DHA in brain remain enigmatic. The metabolism of fatty acids at the cellular level is controlled, in part, by a family of enzymes called Acyl‐CoA Synthetases (ACSs) which perform an energy‐requiring reaction that constitutes the first and required step for nearly every cellular lipid metabolic pathway. Of the identified ACSs, one in particular, Acsl6, appears to be brain specific and its manipulation has been shown to regulate DHA metabolism in vitro. To determine the role of Acsl6 in vivo, we generated a conditional Acsl6‐deficient mouse model (Acsl6−/−). The loss of mouse Acsl6 decreases cerebellar DHA‐containing phospholipid species by 35–72%, and increases arachidonic acid‐, an omega‐6 fatty acid, containing phospholipids 120–200%. Despite the loss of DHA in brain phospholipids, the Acsl6−/− and control inflammatory response to an acute pro‐inflammatory lipopolysaccharide intraperitoneal injection was similar. However, Acsl6−/− mice present with motor dysfunction as evidenced by impaired performance in a wire hang test and reduce startle response to acoustic stimuli. Acsl6−/− brains have reduced glutathione, increased mRNA expression of the oxidative stress‐related transcription factor Nrf2, and increased GFAP protein abundance. Together these data suggest that ACSL6 is required for enriching the brain with the neuroprotective omega‐3 fatty acid, DHA, and that the loss of Acsl6 impairs motor function, increases oxidative stress and promotes astrocyte reactivity in the brain.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.