Abstract
Enhanced production of monounsaturated fatty acids (FA) derived from carbohydrate-enriched diets has been implicated in the development of obesity and insulin resistance. The FA elongases Elovl-5 and Elovl-6 are regulated by nutrient and hormone status, and have been shown using intact yeast and mammalian microsome fractions to be involved in the synthesis of monounsaturated FAs (MUFA). Herein, targeted knockdown and overexpression of Elovl-5 or Elovl-6 was used to determine their roles in de novo synthesis of specific MUFA species in mammalian cells. Treatment of rat insulinoma (INS)-1 cells with elevated glucose increased de novo FA synthesis and the ratio of MUFAs to saturated FAs. Elovl-5 knockdown decreased elongation of 16:1,n-7. Elovl-5 overexpression increased synthesis of 18:1,n-7; however, this increase was dependent on stearoyl-CoA desaturase-driven 16:1,n-7 availability. Knockdown of Elovl-6 decreased elongation of 16:0 and 16:1,n-7, resulting in accumulation of 16:1,n-7. Elovl-6 overexpression preferentially drove synthesis of 16:0 elongation products 18:0 and 18:1,n-9 but not 18:1,n-7. These findings demonstrate that coordinated induction of FA elongase and desaturase activity is required for balanced synthesis of specific n-7 versus n-9 MUFA species. Given the relative abundance of 16:0 to 16:1,n-7 and the specificity of Elovl-6 for 16:0, Elovl-6 is a major elongase for 18:1,n-9 production.
Highlights
Enhanced production of monounsaturated fatty acids (FA) derived from carbohydrate-enriched diets has been implicated in the development of obesity and insulin resistance
This study presents a comprehensive analysis of the effects of both decreased and increased expression of fatty acid elongase (Elovl)-5, Elovl-6, and stearoyl-CoA desaturase (SCD) on FAs synthesized de novo from glucose in a mammalian cell line
INS-1 cells were selected as a model because they exhibit increased lipogenic gene expression and triacylglyceride storage in response to elevated glucose or liver X receptor (LXR) activation [20,21,22] and are currently being used to study the impact of FA elongases and desaturases on palmitate-induced endoplasmic reticulum (ER) stress and apoptosis
Summary
Enhanced production of monounsaturated fatty acids (FA) derived from carbohydrate-enriched diets has been implicated in the development of obesity and insulin resistance. Elovl-6 overexpression preferentially drove synthesis of 16:0 elongation products 18:0 and 18:1,n-9 but not 18:1,n-7 These findings demonstrate that coordinated induction of FA elongase and desaturase activity is required for balanced synthesis of specific n-7 versus n-9 MUFA species. 16:1,n-7 was recently identified as an adipose tissue-derived lipid hormone capable of enhancing muscle insulin sensitivity [10] These findings emphasize the importance of understanding the mechanisms regulating the production of MUFAs. Synthesis of FAs de novo involves the enzymes acetylCoA carboxylase (ACC) and fatty acid synthase (FAS) that carboxylate cytosolic acetyl-CoA to malonyl-CoA and covalently bond malonyl-CoA C2 units to produce the C16 FA palmitate (16:0), respectively [11].
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