title: Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice.
abstract: 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.affiliation: Nutrition Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, OR, USA.
authors.forename: Sasmita
authors.initials: S
authors.lastname: Tripathy
authors.forename: Donald B
authors.initials: DB
authors.lastname: Jump
mesh_terms: D000123:Acetyltransferases / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D000081031:Fatty Acid Elongases; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis / Q000187:drug effects; D018149:Glucose Intolerance / Q000150:complications; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D009829:Oleic Acids / Q000096:biosynthesis* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C000630954:ELOVL5 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D018942:Macrolides; D046912:Multiprotein Complexes; D009829:Oleic Acids; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C525637:rictor protein, mouse; C086151:soraphen A; D000123:Acetyltransferases; C581235:Elovl5 protein, mouse; D000081031:Fatty Acid Elongases; C494922:Akt2 protein, mouse; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C050413:11-octadecenoic acid