Short-Chain Fatty Acid Receptors and Cardiovascular Function

Abstract

Increasing experimental and clinical evidence points toward a very important role for the gut microbiome and its associated metabolism in human health and disease, including in cardiovascular disorders. Free fatty acids (FFAs) are metabolically produced and utilized as energy substrates during almost every biological process in the human body. Contrary to long- and medium-chain FFAs, which are mainly synthesized from dietary triglycerides, short-chain FFAs (SCFAs) derive from the gut microbiota-mediated fermentation of indigestible dietary fiber. Originally thought to serve only as energy sources, FFAs are now known to act as ligands for a specific group of cell surface receptors called FFA receptors (FFARs), thereby inducing intracellular signaling to exert a variety of cellular and tissue effects. All FFARs are G protein-coupled receptors (GPCRs) that play integral roles in the regulation of metabolism, immunity, inflammation, hormone/neurotransmitter secretion, etc. Four different FFAR types are known to date, with FFAR1 (formerly known as GPR40) and FFAR4 (formerly known as GPR120) mediating long- and medium-chain FFA actions, while FFAR3 (formerly GPR41) and FFAR2 (formerly GPR43) are essentially the SCFA receptors (SCFARs), responding to all SCFAs, including acetic acid, propionic acid, and butyric acid. As with various other organ systems/tissues, the important roles the SCFARs (FFAR2 and FFAR3) play in physiology and in various disorders of the cardiovascular system have been revealed over the last fifteen years. In this review, we discuss the cardiovascular implications of some key (patho)physiological functions of SCFAR signaling pathways, particularly those regulating the neurohormonal control of circulation and adipose tissue homeostasis. Wherever appropriate, we also highlight the potential of these receptors as therapeutic targets for cardiovascular disorders.

Keywords: FFAR2; FFAR3; GPCR; SCFA; adipose tissue; cardiovascular; hormone secretion; neuronal; signal transduction; sympathetic.

Figure 1

The cardiovascular physiology relevant to FFAR2 signaling. AC: Adenylyl cyclase; DAG: Diacylglycerol; ERK: Extracellular signal-regulated (mitogen-activated protein, MAP) kinase; IP₃: Inositol 1′, 4′, 5′-trisphosphate; PLC: Phospholipase C; PKC: Protein kinase C; “???” indicates a lack of consensus (currently) for the action depicted. (See text for details and for all other molecular acronym descriptions.)

Figure 2

The cardiovascular physiology relevant to FFAR3 signaling. BP: Blood pressure; ERK: Extracellular signal-regulated (mitogen-activated protein, MAP) kinase; HR: Heart rate; IP₃: Inositol 1′, 4′, 5′-trisphosphate; NE: Norepinephrine (noradrenaline); P: Phosphorylation; RGS4: Regulator of G protein signaling protein-4; SGLT2i: Sodium-glucose co-transporter type 2 inhibitor; SNS: Sympathetic nervous system; “???” indicates a signaling mechanism that is (currently) unknown. (See text for details and for all other molecular acronym descriptions.)