Docosahexaenoic acid antagonizes the boosting effect of palmitic acid on LPS inflammatory signaling by inhibiting gene transcription and ceramide synthesis

Abstract

It is well known that saturated fatty acids (SFAs) and unsaturated fatty acid, in particular omega-3 polyunsaturated fatty acids (n-3 PUFAs), have different effects on inflammatory signaling: SFAs are pro-inflammatory but n-3 PUFAs have strong anti-inflammatory properties. We have reported that palmitic acid (PA), a saturated fatty acid, robustly amplifies lipopolysaccharide (LPS) signaling to upregulate proinflammatory gene expression in macrophages. We also reported that the increased production of ceramide (CER) via sphingomyelin (SM) hydrolysis and CER de novo synthesis plays a key role in the synergistic effect of LPS and PA on proinflammatory gene expression. However, it remains unclear if n-3 PUFAs are capable of antagonizing the synergistic effect of LPS and PA on gene expression and CER production. In this study, we employed the above macrophage culture system and lipidomical analysis to assess the effect of n-3 PUFAs on proinflammatory gene expression and CER production stimulated by LPS and PA. Results showed that DHA strongly inhibited the synergistic effect of LPS and PA on proinflammatory gene expression by targeting nuclear factor kappa B (NFκB)-dependent gene transcription. Results also showed that DHA inhibited the cooperative effect of LPS and PA on CER production by targeting CER de novo synthesis, but not SM hydrolysis. Furthermore, results showed that myriocin, a specific inhibitor of serine palmitoyltransferase, strongly inhibited both LPS-PA-stimulated CER synthesis and proinflammatory gene expression, indicating that CER synthesis is associated with proinflammatory gene expression and that inhibition of CER synthesis contributes to DHA-inhibited proinflammatory gene expression. Taken together, this study demonstrates that DHA antagonizes the boosting effect of PA on LPS signaling on proinflammatory gene expression by targeting both NFκB-dependent transcription and CER de novo synthesis in macrophages.

Ceramide and palmitic acid inhibit macrophage-mediated epithelial–mesenchymal transition in colorectal cancer

“…Thus, macrophage function and phenotype are highly dependent on their microenvironment [40]. Lipids (cellular or dietary) and alterations in lipid metabolism have long been identified as regulators of immune cell function and macrophage polarization [27,[41][42][43][44]. Consistent with previous reports, our data demonstrate that PA and Cer attenuate the M2-phenotype in macrophages.…”

“…Albeit being different lipid species, PA and Cer block M2-TAM polarization. Previous studies demonstrated that Cer is synthesized upon PA-amplified LPS-signaling, and stimulates the transcription of pro-inflammatory cytokines [43,47]. Thus, it is likely that addition of Cer, a downstream signaling mediator of PA-mediated TLR signaling, directly stimulates the same pro-inflammatory response as PA.…”

The Short Overview on the Relevance of Fatty Acids for Human Cardiovascular Disorders

“…The results revealed that palmitic acid is related to a higher risk of death from CVD. Palmitic FA, by enhancing inflammation-related signaling of lipopolysaccharides in macrophages, promotes inflammation and the development of CVD [34][35][36]. In addition, inflammatory activity probably is characterized by increased production of pro-inflammatory cytokines and oxidants, leading to cellular hypertrophy and apoptosis.…”

Flaxseed Oil or n‐7 Fatty Acid‐Enhanced Fish Oil Supplementation Alters Fatty Acid Composition, Plasma Insulin and Serum Ceramide Concentrations, and Gene Expression in Lambs

“…In bovine primary adipocyte cultures, Rico et al (2018) reported that ceramides are involved in the inhibitory pathway of insulin-stimulated glucose uptake through the downregulation of protein kinase B, AKT. While the exact mechanism by which palmitoleic acid could reduce ceramide synthesis is not known, we hypothesize that it can exert similar ceramidelowering effects similar to other MUFA like oleic acid (Jin et al, 2018). Oleic acid reduces ceramide accumulation with the simultaneous induction of mitochondrial FA oxidation and the reduction of inflammatory signals, both of which can improve insulin signaling (Palomer et al, 2018).…”