Fatty acid biosynthesis from glutamate and glutamine is specifically induced in neuronal cells under hypoxia

Hypoxia is involved in many neuronal and non-neuronal diseases, and defining the mechanisms for tissue adaptation to hypoxia is critical for the understanding and treatment of these diseases. One mechanism for tissue adaptation to hypoxia is increased glutamine and/or glutamate (Gln/Glu) utilization. To address this mechanism, we determined incorporation of Gln/Glu and other lipogenic substrates into lipids and fatty acids in both primary neurons and a neuronal cell line under normoxic and hypoxic conditions and compared this to non-neuronal primary cells and non-neuronal cell lines. Incorporation of Gln/Glu into total lipids was dramatically and specifically increased under hypoxia in neuronal cells including both primary (2.0- and 3.0-fold for Gln and Glu, respectively) and immortalized cultures (3.5- and 8.0-fold for Gln and Glu, respectively), and 90% to 97% of this increase was accounted for by incorporation into fatty acids (FA) depending upon substrate and cell type. All other non-neuronal cells tested demonstrated decreased or unchanged FA synthesis from Gln/Glu under hypoxia. Consistent with these data, total FA mass was also increased in neuronal cells under hypoxia that was mainly accounted for by the increase in saturated and monounsaturated FA with carbon length from 14 to 24. Incorporation of FA synthesized from Gln/Glu was increased in all major lipid classes including cholesteryl esters, triacylglycerols, diacylglycerols, free FA, and phospholipids, with the highest rate of incorporation into triacylglycerols. These results indicate that increased FA biosynthesis from Gln/Glu followed by esterification may be a neuronal specific pathway for adaptation to hypoxia. We identified a novel neuronal specific pathway for adaptation to hypoxia through increased fatty acid biosynthesis from glutamine and glutamate (Gln/Glu) followed by esterification into lipids. All other non-neuronal cells tested demonstrated decreased or unchanged lipid synthesis from Gln/Glu under hypoxia. Incorporation of other lipogenic substrates into lipids was decreased under hypoxia in neuronal cells. We believe that this finding will provide a novel strategy for treatment of oxygen and energy deficient conditions in the neuronal system.