Deletion of ELOVL6 blocks the synthesis of oleic acid but does not prevent the development of fatty liver or insulin resistance

Abstract

Elongation of very long chain fatty acid-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. Our previous in vitro studies suggested that ELOVL6 elongated long-chain saturated fatty acids and monounsaturated fatty acids with chain lengths of 12 to 16 carbons. Here, we describe the generation and phenotypic characterization of Elovl6−/− mice. As predicted from the in vitro studies, 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 (C16:0). Unexpectedly, Elovl6−/− mice produced vaccenic acid (C18:1, n-7), the elongated product of palmitoleate (C16:1, n-7), suggesting that palmitoleate (C16:1, n-7) to vaccenate (C18:1, n-7) elongation was not specific to ELOVL6. The only detected consequence of deleting Elovl6−/− in 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 (C16:1, n-7) and vaccenic (C18:1, n-7) acids can largely replace the roles of oleic acid (C18:1, n-9) in vivo and that the deletion of ELOVL6 does not protect mice from the development of hepatic steatosis or insulin resistance.

Liver Fatty Acid Composition and Inflammation in Mice Fed with High-Carbohydrate Diet or High-Fat Diet

“…In rodents, about 90% of the stearic acid is synthesized from palmitic acid by elongase activity [29]. In accordance, mice fed with HFD, presenting high ( p < 0.05) elongase activity, also had higher stearic acid levels (Table 2).…”

“…Moon et al [29] have reported accumulation of palmitic acid, palmitoleic acid and reduced contents of stearic acid and oleic acid in knockout mice for this enzyme.…”

Effect of high carbohydrate diet on elongase and desaturase activity and accompanying gene expression in rat’s liver

“…The most important changes concern metabolism of 16:0 and 18:0 as a dominant products of DNL [30]. Both FAs are subjects to elongation or desaturation processes [33]. On the basis of our observation, the desaturation is a main process of 16:0 and 18:0 metabolism in liver of rat fed HiCHO diet because of a higher expression of mRNA for Scd1 (Fig.…”

Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease

“…Studies utilizing genetic or adenoviral overexpression of Elovl6, reported development of liver inflammation and progression to NASH (77). However, a more recent study of global Elovl6 knockout did not confirm these findings (78), perhaps explaining why liver specific Elovl6 mice have yet to be reported.…”