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

Oregon State University, United States.
The Journal of Lipid Research (Impact Factor: 4.73). 10/2012; DOI: 10.1194/jlr.M028787
Source: PubMed

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. 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.

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    ABSTRACT: Fibrates have been reported to elevate the hepatic proportion of oleic acid (18:1n-9) through inducing stearoyl-CoA desaturase (SCD). Despite abundant studies on the regulation of SCD in the liver, little is known about this issue in the small intestine. The present study aimed to investigate the effect of clofibric acid on the fatty acid profile, particularly monounsaturated fatty acids (MUFA), and the SCD expression in intestinal mucosa. Treatment of rats with a diet containing 0.5 % (w/w) clofibric acid for 7 days changed the MUFA profile of total lipids in intestinal mucosa; the proportion of 18:1n-9 was significantly increased, whereas those of palmitoleic (16:1n-7) and cis-vaccenic (18:1n-7) acids were not changed. Upon the treatment with clofibric acid, SCD was induced and the gene expression of SCD1, SCD2, and fatty acid elongase (Elovl) 6 was up-regulated, but that of Elovl5 was unaffected. Fat-free diet feeding for 28 days increased the proportions of 16:1n-7 and 18:1n-7, but did not effectively change that of 18:1n-9, in intestinal mucosa. Fat-free diet feeding up-regulated the gene expression of SCD1, but not that of SCD2, Elovl6, or Elovl5. These results indicate that intestinal mucosa significantly changes its MUFA profile in response to challenges by clofibric acid and a fat-free diet and suggest that up-regulation of the gene expression of SCD along with Elovl6 is indispensable to elevate the proportion of 18:1n-9 in intestinal mucosa.
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    ABSTRACT: Elongation of Very Long Chain Fatty Acids Like family member 6 (ELOVL6) is a fatty acyl elongase that performs the initial and rate-limiting condensing reaction required for microsomal elongation of long chain fatty acids (C12-16). Here, we describe the generation and phenotypic characterization of Elovl6-/- mice. Livers from Elovl6-/- mice accumulated palmitic (C16:0) and palmitoleic (C16:1, n-7) fatty acids and contained significantly less stearic (C18:0) and oleic (C18:1, n-9) acids, confirming that ELOVL6 is the only enzyme capable of elongating palmitate. Unexpectedly, Elovl6-/- mice produced vaccenic (C18:1, n-7) acid, the elongated product of palmitoleate, suggesting that palmitoleate to vaccenate elongation was not specific to ELOVL6. The only detected consequence of deleting Elovl6-/- mice was that their livers accumulated significantly more triglycerides than wild-type mice when fed a fat-free/high carbohydrate diet. When mice were fed a high fat diet or ELOVL6 was deleted in ob/ob mice, the absence of ELOVL6 did not alter the development of obesity, fatty liver, hyperglycemia, or hyperinsulinemia. Combined, these results suggest that palmitoleic and vaccenic acid can largely replace the roles of oleic acid in vivo and that the deletion of ELOVL6 does not protect mice from the development of hepatic steatosis or insulin resistance.
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