Elovl5 Regulates the mTORC2-Akt-FOXO1 Pathway by Controlling Hepatic cis-Vaccenic Acid Synthesis in Diet-Induced Obese Mice Public Deposited

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  • Elevated hepatic expression of fatty acid elongase-5 (Elovl5) induces FoxO1 phosphorylation, lowers FoxO1 nuclear content and suppresses expression of genes involved in gluconeogenesis. In this report we define the molecular and metabolic basis of Elovl5 control of FoxO1 phosphorylation. Adenoviral-mediated (Ad-Elovl5) induction of hepatic Elovl5 in diet induced obese-glucose intolerant mice and HepG2 cells increased the phosphorylation of Akt2-S⁴⁷³ (mTORC2 site), but not Akt2-T³⁰⁸ (PDK1 site). The Akt2 inhibitor, Akti1/2, blocked Elovl5 induction of FoxO1-S²⁵⁶ phosphorylation in HepG2 cells. Elevated Elovl5 activity in liver and HepG2 cells induced rictor mRNA, rictor protein and rictor-mTOR interaction, while rictor knockdown (siRNA) attenuated Elovl5 induction of Akt2-S⁴⁷³ and FoxO1-S²⁵⁶ phosphorylation in HepG2 cells. Fatty acid analysis revealed that the abundance of cis-vaccenic acid (18:1,n-7) was increased in livers of obese mice and HepG2 cells following Ad-Elovl5 infection. Treating HepG2 cells with Elovl5 substrates established that palmitoleic acid (16:1,n-7), but not γ-linolenic acid (18:3,n-6), induced rictor protein, Akt-S⁴⁷³ and FoxO1- S²⁵⁶ phosphorylation. Inhibition of fatty acid elongation blocked 16:1,n-7, but not 18:1,n- 7, induction of rictor protein and Akt-S⁴⁷³ and FoxO1-S²⁵⁶ phosphorylation. These results establish a novel link between Elovl5 mediated synthesis of 18:1,n-7 and gluconeogenesis through the control of the mTORC2-Akt-FoxO1 pathway.
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  • Tripathy, S., & Jump, D. B. (2013). Elovl5 regulates the mTORC2-akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice. Journal of Lipid Research, 54(1), 71.
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  • 54
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  • 1
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  • This work was supported by the National Institutes of Health grants (DK 043220 & DK 094600) and the United State Department of Agriculture, National Institute of Food and Agriculture Grant (2009-65200-05846).
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