Alternative splicing of fatty acid desaturases is associated with altered fatty acid composition

Abstract

The delta-6 desaturase, encoded by FADS2, plays a crucial role in omega-3 and omega-6 fatty acid synthesis. We have recently identified an alternative transcript of FADS2 (FADS2 AT1) and 7 alternative transcripts for the putative desaturase FADS3. Here, we investigated regulation of desaturase alternative splicing, and fatty acid changes associated with altered splicing patterns. We hypothesized a role for the splicing repressor PTB/hnRNP I based on bioinformatics predictions of splicing factor binding sites. PTB and FADS2AT1 were inversely correlated in infant baboon tissues, implicating PTB as a major regulator of tissue-specific FADS2 splicing. In human liver-derived HepG2 cells, siRNA knockdown of PTB led to upregulation of FADS2 AT1 and FADS3 AT7. This splicing pattern was associated with a specific decrease in the ratio of total cellular omega-3 to omega-6 fatty acids, including a nearly 2-fold decrease in eicosapentaenoic acid (EPA) content, and a 43% reduction in the ratio of EPA with arachidonic acid (ARA). These findings reveal a novel mechanism controlling availability of eicosanoid precursors for cell signaling. H. R. was supported by a Ruth L. Kirchstein-NRSA predoctoral fellowship in reproductive sciences and genomics (Grant Number T32HD052471) from the National Institutes of Child Health and Human Development.