Document Detail


Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice.
MedLine Citation:
PMID:  23099444     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Elevated hepatic expression of fatty acid elongase-5 (Elovl5) induces FoxO1 phosphorylation, lowers FoxO1 nuclear content, and suppresses expression of genes involved in gluconeogenesis (GNG). 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-S(473) [mammalian target of rapamycin complex-2 (mTORC2) site], but not Akt2-T(308) (PDK1 site). The Akt2 inhibitor Akti1/2 blocked Elovl5 induction of FoxO1-S(256) phosphorylation in HepG2 cells. Elevated Elovl5 activity in liver and HepG2 cells induced rictor mRNA, rictor protein, and rictor-mTOR interaction, whereas rictor knockdown (siRNA) attenuated Elovl5 induction of Akt2-S(473) and FoxO1-S(256) phosphorylation in HepG2 cells. FA 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-S(473), and FoxO1-S(256) phosphorylation. Inhibition of FA elongation blocked 16:1,n-7 but not 18:1,n-7 induction of rictor protein and Akt-S(473) and FoxO1-S(256) phosphorylation. These results establish a novel link between Elovl5-mediated synthesis of 18:1,n-7 and GNG through the control of the mTORC2-Akt-FoxO1 pathway.
Authors:
Sasmita Tripathy; Donald B Jump
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-10-24
Journal Detail:
Title:  Journal of lipid research     Volume:  54     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-17     Completed Date:  2013-05-28     Revised Date:  2014-01-17    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  71-84     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Acetyltransferases / metabolism*
Animals
Carrier Proteins / genetics,  metabolism
Diet / adverse effects*
Forkhead Transcription Factors / metabolism
Gene Knockdown Techniques
Gluconeogenesis / drug effects
Glucose Intolerance / complications
Hep G2 Cells
Humans
Liver / drug effects,  metabolism*,  pathology*
Macrolides / pharmacology
Male
Mice
Mice, Inbred C57BL
Multiprotein Complexes / metabolism
Obesity / complications,  etiology,  metabolism*,  pathology
Oleic Acids / biosynthesis*,  metabolism
Phosphorylation / drug effects
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction* / drug effects
TOR Serine-Threonine Kinases / metabolism
Grant Support
ID/Acronym/Agency:
DK-043220/DK/NIDDK NIH HHS; DK-094600/DK/NIDDK NIH HHS; R01 DK094600/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Carrier Proteins; 0/Forkhead Transcription Factors; 0/Foxo1 protein, mouse; 0/Macrolides; 0/Multiprotein Complexes; 0/Oleic Acids; 0/TOR complex 2; 0/rictor protein, mouse; 122547-72-2/soraphen A; 143-25-9/11-octadecenoic acid; EC 2.3.1.-/Acetyltransferases; EC 2.3.1.-/Elovl5 protein, mouse; EC 2.3.1.-/fatty acid elongases; EC 2.7.1.1/TOR Serine-Threonine Kinases; EC 2.7.11.1/Akt2 protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections

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