Elovl5 Regulates the mTORC2-Akt-FOXO1 Pathway by Controlling Hepatic cis-Vaccenic Acid Synthesis in Diet-Induced Obese Mice.
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 gamma-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.
- "Although the precise molecular event triggered by FASN that is responsible for Rictor regulation remains poorly defined, our present data indicate that FASN does not affect mRNA levels of Rictor, but acts post-transcriptionally. In addition, despite a recent report showing that Rictor levels are modulated by ELOVL5 in HepG2 cells , our data seem to exclude that FASN acts via ELOVL5 in liver cancer cells both in vivo and in vitro. "
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ABSTRACT: Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population. Expected final online publication date for the Annual Review of Nutrition Volume 33 is July 17, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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ABSTRACT: The Goto-Kakizaki (GK) rat is an animal model for spontaneous-onset, non-obese type 2 diabetes. Despite abundant evidence about disorders in metabolism, little information is available about fatty acid metabolism in the liver of GK rats. This study aimed to investigate the characteristics of the fatty acid profile, particularly MUFA, and the mechanism underlying the alterations in fatty acid profiles in the liver of GK rats. The activities of enzymes that participate in the biosynthesis of MUFA, expressions of genes encoding these enzymes, and the fatty acid profile in the liver were compared with those of obese Zucker (fa/fa) (ZF) rats, which are obese and non-diabetic. Stearoyl-CoA desaturase (SCD) activity and SCD1 gene expression were considerably up-regulated in GK rats, and these levels were largely comparable to those in ZF rats. However, the proportions and contents of oleic acid and palmitoleic acid were very low considering the highly elevated activity of SCD in the liver of GK rats, when compared with ZF rats. Palmitoyl-CoA chain elongation (PCE) activity and fatty acid elongase (Elovl6) gene expression were markedly up-regulated in ZF rats, whereas PCE activity was up-regulated much less and Elovl6 gene expression was unchanged in GK rats. These results suggest the possibility that up-regulation of gene expression of Elovl6 along with SCD1 is indispensable to elevate the proportions and contents of oleic acid in the liver.
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