Synthesis of DHA (omega-3 fatty acid): FADS2 gene polymorphisms and regulation by PPARα

Didier Majou

doi:10.1051/ocl/2021030

Abstract

In humans, in several biological systems, in particular the nervous system, the FADS2 gene transcribes Δ6-desaturase, which is the rate-limiting enzyme for converting α-linolenic acid into docosahexaenoic acid (an n-3 fatty acid). The peroxisome proliferator-activated receptor α (PPARα) modulates the transcription of FADS2 gene by interacting with a second transcription factor: the retinoid X receptor α (RXRα). These transcription factors take the form of a PPARα-RXRα heterodimer and are modulated by the ligands that modify their respective structures and enable them to bind to the peroxisome proliferator response element (PPRE) located in the promoter region of the FADS2 gene. Free estradiol induces the activation of PPARα via two pathways (i) transcription through genomic action mediated by an estrogen receptor; (ii) a non-genomic effect that allows for phosphorylation and activates PPARα via the ERK1/2-MAPK pathway. Phosphorylation is an on/off switch for PPARα transcription activity. Since Δ6-desaturase expression is retro-inhibited by free intracellular DHA in a dose-dependent manner, this position paper proposes an original hypothesis: if DHA simultaneously binds to both phosphorylated PPARα and RXRα, the resulting DHA-PPARαP-RXRα-DHA heterodimer represses FADS2 gene via PPRE. The retinoic acids-RARα-RXRα-DHA heterodimer would not dissociate from corepressors and would prevent coactivators from binding to FADS2. We speculate that SNPs, which are mostly located on PPRE, modulate the binding affinities of DHA-PPARαP-RXRα-DHA heterodimer to PPRE. The DHA-PPARαP-RXRα-DHA heterodimer’s greater affinity for PPRE results in a decreased production of D6D and DHA. FADS2 promoter polymorphism would increase the competition between DHA and other ligands, in accordance with their concentrations and affinities.

Highlights

In humans, the D6-desaturase gene, a FADS2 gene is located on chromosome 11 (11q12–13.1) and is ubiquitously expressed, especially in the liver and brain (Innis and Dyer, 2002; Nakamura and Nara, 2004), as well as in heart skeletal muscle, kidney, lung, prostate, testes, adipocytes, ovary, uterus and sebaceous glands (Ge et al, 2003; Nwankwo et al, 2003; Pédrono et al, 2010)
These transcription factors take the form of a PPARaRXRa heterodimer, located within the nucleus and are modulated by ligands that modify their tertiary structures, and enable them to bind to the peroxisome proliferator response element (PPRE) located in the promoter region of the FADS2 gene
It has been suggested that estradiol may increase the activity of the desaturation pathway because docosahexaenoic acid (DHA) synthesis has been shown to be almost 3 times greater in women who take oral contraceptive pills that contain ethinylestradiol than in women who do not, while testosterone stimulus decreases DHA status (Giltay et al, 2004). This difference in conversion appears to be associated with estrogen and some evidence indicates that the expression of enzymes, including desaturases, involved in synthesizing DHA from a-linolenic acid (ALA) is higher in females

Summary

Introduction

The D6-desaturase gene, a FADS2 (fatty acid desaturase 2) gene is located on chromosome 11 (11q12–13.1) and is ubiquitously expressed, especially in the liver and brain (astrocytes) (Innis and Dyer, 2002; Nakamura and Nara, 2004), as well as in heart skeletal muscle, kidney, lung, prostate, testes, adipocytes, ovary, uterus and sebaceous glands (Ge et al, 2003; Nwankwo et al, 2003; Pédrono et al, 2010). D6D is the rate-limiting enzyme for converting a-linolenic acid (ALA) into docosahexaenoic acid (DHA) (n-3 fatty acid) (Fig. 1). This FASD2 enzyme displays a D8-desaturase activity on 20:2 n-6 and 20:3 n-3 which leads respectively to 20:3 n-6 and 20:4 n-3 (Park et al, 2009). The reactivity of the enzyme depends on the concentration of available substrates and their affinity with D6D This is usually expressed as the enzyme’s Km (Michaelis constant), an inverse measure of affinity (Ivanetich et al, 1996; Rodriguez et al, 1998). Dietary n-3 fatty acid intake regulates D6D expression (Cho et al, 1999), but conversion to DHA is limited (Burdge, 2006). This position paper aims to highlight the possible mechanisms involved À active molecules and transcription factors À while considering the impact of single-nucleotide FADS2 promoter polymorphisms

Regulation of the FADS2 gene

PPARa-RXRa regulation mechanisms governing the FADS2 gene

Promoter polymorphisms of the FADS2 gene and their consequences

Findings

Conclusion