Fatty Acid Metabolism Disruptions: A Subtle yet Critical Factor in Adverse Pregnancy Outcomes

Abstract

The establishment and maintenance of pregnancy encompass a series of complex and high-energy-consuming physiological processes, resulting in a significant energy demand. Fatty acids, one of the most essential nutrients, play a crucial role in energy supply via oxidation and perform critical biological functions such as anti-inflammatory and anti-oxidant effects, which substantially impact human health. Disordered fatty acid metabolism can cause anomalies in fetal growth and development, as well as a range of pregnancy problems, which can influence the health of both the mother and the fetus. In this review, we innovatively explore the relationship between fatty acid metabolism abnormalities and pregnancy complications, emphasizing the potential of dietary interventions with polyunsaturated fatty acids in improving pregnancy outcomes. These findings provide important evidence for clinical interventions and enhance the understanding and practical application of health management during pregnancy.

Keywords: fatty acid oxidation; inflammation; omega-3 fatty acids; oxidative stress; pregnancy outcomes.

Figure 1

The biosynthesis pathways of n-3 and n-6 PUFAs . N-3 and n-6 PUFAs undergo a series of biosynthetic processes utilizing the same desaturases and elongases. Stearic acid is a lipid mediator from C18 polyunsaturated fatty acids, such as ALA or LA. Eicosanoids are formed from C20 polyunsaturated fatty acids, such as DGLA, ARA, or EPA. Docosanoids are synthesized from C22 polyunsaturated fatty acids, such as DPAn-3 and DHA. The n-3 and n-6 PUFAs undergo metabolism via LOX, COX, and CYP pathways. These processes can transform EPA and DHA into specialized proresolving mediators (SPMs), such as resolvins, maresins, and protectins, which possess anti-inflammatory characteristics . AA: Arachidonic acid; AdA: Adrenal acid; ALA: α-Linolenic acid; DHA: Docosahexaenoic acid; DHLA: Dihydrolipoic acid; DHEA: Docosahexaenoyl ethanolamide; DGLA: Dihomo-γ-linolenic acid; DPA: Docosapentaenoic acid; EET: Epoxyeicosatrienoic acid; EPA: Eicosapentaenoic acid; GLA: γ-Linolenic acid; HDoHE: Hydroxydocosahexaenoic acid; HETE: Hydroxy eicosatetraenoic acid; HODE: Hydroxy octadecadienoic acid; HpETE: Hydroperoxy eicosatetraenoic acid; LA: Linoleic acid; LT: Leukotriene; LX: Lipoxin; PG: Prostaglandin; Rv: Resolvin; SDA: Stearidonic acid; TX: Thromboxane.

Figure 2

Four main stages of fatty acid β-oxidation. VLCFAs start β-oxidation in peroxisomes, while MCFAs and LCFAs initiate β-oxidation in mitochondria. Dietary PUFAs and endogenously produced FA precursors can undergo conventional elongation and desaturation processes, forming compounds that can be integrated into cellular membranes. Phospholipase A2 can break down phospholipids in cell membranes, releasing PUFAs. Lipid peroxidation is when oxidizing agents, such as free radicals and reactive oxygen species (ROS), react with FAs with double bonds, especially PUFAs. Enzymatic or non-enzymatic processes can both mediate this process. VLCFA: Very Long-Chain Fatty Acids; MCFA: Medium-Chain Fatty Acids; LCFA: ong-Chain Fatty Acids; ACS: Acyl-CoA Synthetase; FA-CoA: Fatty Acyl-CoA; ABCD: Very Long-Chain Acyl-CoA Transporter; CPT: Carnitine Palmitoyl Transferase; CAT: Carnitine Acylcarnitine Translocase; C16:0-CoA: Initial product of fatty acid synthesis.

Figure 3

Gestational complications reflect the continuity of placental dysfunction, and n-3 PUFAs may improve pregnancy outcomes through their anti-inflammatory and antioxidant effects. The primary mechanisms of the anti-inflammatory action of n-3 PUFAs include: A) N-3 PUFAs produce SPMs via the LOX and COX pathways ; B) N-3 PUFAs inhibit the phosphorylation of the inhibitory subunit IκB of NFκB, leading to reduced activation of the pro-inflammatory transcription factor NFκB. N-3 PUFAs also compete with lipopolysaccharides (LPS) and saturated fatty acids (SFA) to bind and activate toll-like receptors, such as TLR-4, inhibiting the activation of NF-κB ; C) N-3 PUFAs suppress the activation of the NLRP3 inflammasome through GPR40 and GPR120-dependent pathways . Research on the anti-oxidant mechanisms of n-3 PUFAs is relatively limited, but can currently be summarized as follows , , : D) N-3 PUFAs can improve the status of peroxidases, such as increasing the activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px); E) N-3 PUFAs can lower levels of phagocyte and tissue-specific NADPH oxidases (NOX), which are significant contributors to ROS production. N-3 PUFAs may also inhibit NOX generation by competing to reduce the synthesis of AA, a primary activator of NOX; F) DHA can enhance the expression of antioxidant-related genes (such as SIRT1 and BRCA1/MSH2), which are crucial for DNA repair.