Fig. 1

FAs as metabokines at a molecular level. SCFAs, MCFAs, LCFAs, and essential PUFAs are mostly obtained from diet, whereas LCFAs can also be synthesized de novo which requires the participation of rate-limiting enzymes, such as acetyl-CoA carboxylases1 (ACC1). The FA β-oxidation process starts with the translocation into mitochondrion assisted by critical transporter carnitine palmitoyl-transferase 1/2 (CPT1/2). The extensive regulatory role of FAs derives from generally five ways of action. (1) FAs are energy substrates that produce NADH, acetyl-CoA, and FADH₂ to support the Krebs cycle and oxidative phosphorylation in the mitochondrion. (2) FAs are responsible for membrane dynamics and through the alteration of FA level and composition regulate local membrane biological functions. (3) FAs activate various membrane and nuclear receptors including GPCRs, TLRs, PPARs, affecting downstream signaling pathways. (4) FAs, especially short-chain FAs, are potent histone deacetylase (HDAC) inhibitors capable of regulating histone or non-histone acetylation to modulate the expression and stability of transcripts and proteins. (5) FAs through metabolism generate downstream lipid mediators, widely participating in the maintenance and resolution of chronic inflammation