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.

Regulator of G-Protein Signaling-4 Attenuates Cardiac Adverse Remodeling and Neuronal Norepinephrine Release-Promoting Free Fatty Acid Receptor FFAR3 Signaling

“…Although both NE and epinephrine mediate the effects of the sympathetic nervous system on all cells and tissues, NE is the neurotransmitter synthesized, stored, and released from sympathetic neurons, whereas epinephrine is a hormone synthesized in the adrenal medulla and secreted into the systemic circulation [ 39 , 40 , 41 ]. FFAR3 knockout mice display significantly lower catecholamine synthesis, as evidenced by tyrosine hydroxylase downregulation, the enzyme that catalyzes the rate-limiting step of catecholamine biosynthesis [ 42 ], as well as lower sympathetic neuronal firing rate and heart rate [ 1 , 4 ].…”

“…The short-chain free fatty acid (SCFA) propionate stimulates cellular signaling primarily via two different G-protein-coupled receptors (GPCRs) and free fatty acid receptor (FFAR)-2 and -3 [ 1 , 2 , 3 ]. FFAR3, also known as GPR41, regulates cardiovascular function via effects in peripheral sympathetic neurons, wherein it promotes neuronal firing and norepinephrine (NE) synthesis and release [ 4 , 5 ].…”

“…FFAR3 is expressed in various tissues including in the heart [ 1 , 2 , 3 ] and is known to promote tissue inflammation and, as mentioned above, sympathetic nervous system (SNS) activity, neuronal firing, and NE release [ 1 , 2 , 3 ]. The latter is cardiotoxic, especially for the failing heart, as it increases myocardial oxygen/metabolic demand [ 24 , 25 ].…”

The role of the gut microbiota in health and cardiovascular diseases

“…It is notable that gut microbiota could serve as a protective regulator against CAD development by synthesizing SCFAs [ 390 , 391 ]. In a cohort study with 405 subjects, authors reported the abundance of Roseburia intestinalis and Faecalibacterium cf.…”

The content of saturated fatty acids in the blood plasma of cows in the winter period depends on autonomic nervous regulation

“…Підвищення використання жирних кислот пропорційно впливу навантаження, стресу та ін. Сталість вільних жирних кислот в організмі постійно коливається (Lymperopoulos et al, 2022;Vanacker et al, 2022). Цьому може посприяти вплив автономної нервової системи, що буде розглянуто в даній статі.…”