Short-chain fatty acids are potential goalkeepers of atherosclerosis

Abstract

Short-chain fatty acids (SCFAs) are metabolites produced by gut bacteria and play a crucial role in various inflammatory diseases. Increasing evidence suggests that SCFAs can improve the occurrence and progression of atherosclerosis. However, the molecular mechanisms through which SCFAs regulate the development of atherosclerosis have not been fully elucidated. This review provides an overview of the research progress on SCFAs regarding their impact on the risk factors and pathogenesis associated with atherosclerosis, with a specific focus on their interactions with the endothelium and immune cells. These interactions encompass the inflammation and oxidative stress of endothelial cells, the migration of monocytes/macrophages, the lipid metabolism of macrophages, the proliferation and migration of smooth muscle cells, and the proliferation and differentiation of Treg cells. Nevertheless, the current body of research is insufficient to comprehensively understand the full spectrum of SCFAs' mechanisms of action. Therefore, further in-depth investigations are imperative to establish a solid theoretical foundation for the development of clinical therapeutics in this context.

Keywords: SCFAs; atherosclerosis; endothelium; gut microbiome; immune cells.

FIGURE 1

Mechanisms of SCFA and its ameliorative effects in the development of atherosclerosis. 1. SCFAs bind to G protein-coupled receptors, triggering intracellular signaling cascades, leading to downstream signal transduction activation and the secretion of GLP-1, PYY. SCFA also promotes renin secretion by binding to the receptor Olfr78. 2. SCFAs inhibit HDAC activity, promoting histone acetylation, facilitating the dissociation of DNA from histone octamers and relaxation of chromatin structure. This allows various transcription factors and co-transcription factors to bind specifically to DNA binding sites, activating gene transcription. As ligands for AHR and PPARγ, SCFAs regulate the expression of multiple genes at the transcriptional level through their interaction with these two transcription factors. 3. SCFAs improve atherosclerosis by improving inflammation and oxidative stress of endothelial cells, inhibiting migration of monocytes/macrophages, regulating lipid metabolism of macrophages, regulating proliferation and migration of smooth muscle cells and promoting proliferation and differentiation of Treg cells. SCFAs, short-chain fatty acids; FFAR, free fatty acid receptor; GPR109a, G-protein coupled receptor-109a; Olfr78, olfactory receptor-78; AHR, aryl hydrocarbon receptor; HDAC, histone deacetylase; GLP-1, glucagon-like peptide-1; PYY, peptide YY; NF-κB, Nuclear Factor kappa B; Nrf2, NF-E2-related factor 2; TF, transcription factor. Created with FigDraw (www.figdraw.com).