Free Fatty Acids as Signaling Molecules: Role of Free Fatty Acid Receptors and CD36

Editorial

16 March 2022

Editorial: Free Fatty Acids as Signaling Molecules: Role of Free Fatty Acid Receptors and CD36

Carlos Puebla

Eugenia Morselli

Naim Akhtar Khan

and

Mauricio A. Retamal

3,291 views

5 citations

Editors

Carlos Puebla

Faculty of Life Sciences, Andres Bello University

Eugenia Morselli

Faculty of Medicine and Sciences, San Sebastian University

Mauricio Antonio Retamal

University for Development

Naim Akhtar Khan

Université de Bourgogne

Impact

Review

01 July 2021

Long Chain Fatty Acids as Modulators of Immune Cells Function: Contribution of FFA1 and FFA4 Receptors

Maria A. Hidalgo

, 1 more and

Rafael A. Burgos

Long-chain fatty acids are molecules that act as metabolic intermediates and constituents of membranes; however, their novel role as signaling molecules in immune function has also been demonstrated. The presence of free fatty acid (FFA) receptors on immune cells has contributed to the understanding of this new role of long-chain fatty acids (LCFAs) in immune function, showing their role as anti-inflammatory or pro-inflammatory molecules and elucidating their intracellular mechanisms. The FFA1 and FFA4 receptors, also known as GPR40 and GPR120, respectively, have been described in macrophages and neutrophils, two key cells mediating innate immune response. Ligands of the FFA1 and FFA4 receptors induce the release of a myriad of cytokines through well-defined intracellular signaling pathways. In this review, we discuss the cellular responses and intracellular mechanisms activated by LCFAs, such as oleic acid, linoleic acid, palmitic acid, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), in T-cells, macrophages, and neutrophils, as well as the role of the FFA1 and FFA4 receptors in immune cells.

LCFAs activate signaling pathways and mediate immune cell functions. (A) Oleic and palmitic acids activate intracellular signaling pathways. Oleic acid reduces the release of cytokines, whereas palmitic acid increases the release of cytokines. Linoleic acid reduces viability and inhibits proliferation in T-cells. However, there is no evidence of the participation of the FFA1 receptor in those responses in this cell type. Omega-3 fatty acids inhibit cytokines release, migration, and proliferation. However, the participation of the FFA4 receptor has not been demonstrated in these cells. (B) Oleic and linoleic acids stimulate different signaling pathways and release inflammatory products via the FFA1 receptor in bovine neutrophils. Palmitic acid increases NETosis. However, the role of the FFA1 receptor has not been demonstrated. DHA induces intracellular calcium via the FFA4 receptor in neutrophils and increases release of inflammatory products, independent of the FFA4 receptor. (C) Oleic, linoleic, and palmitic acids activate signaling pathways and stimulate or inhibit the release of inflammatory mediators in macrophages. However, the participation of the FFA1 receptor has not been described yet. Omega-3 fatty acids inhibit intracellular signaling and release of inflammatory products through the FFA4 receptor in macrophages. Solid lines indicate cellular responses induced by fatty acids in which the participation of the FFA receptor has been demonstrated. Dashed lines represent responses induced by fatty acids where there is no evidence of the participation of the FFA receptors. Question marks indicate that FFA receptor involvement has not been demonstrated or FFA receptors have not been detected (created with BioRender.com).

20,519 views

81 citations

Mini Review

24 May 2021

Use of Short-Chain Fatty Acids for the Recovery of the Intestinal Epithelial Barrier Affected by Bacterial Toxins

Diliana Pérez-Reytor

, 2 more and

Katherine García

Short-chain fatty acids (SCFAs) are carboxylic acids produced as a result of gut microbial anaerobic fermentation. They activate signaling cascades, acting as ligands of G-protein-coupled receptors, such as GPR41, GPR43, and GPR109A, that can modulate the inflammatory response and increase the intestinal barrier integrity by enhancing the tight junction proteins functions. These junctions, located in the most apical zone of epithelial cells, control the diffusion of ions, macromolecules, and the entry of microorganisms from the intestinal lumen into the tissues. In this sense, several enteric pathogens secrete diverse toxins that interrupt tight junction impermeability, allowing them to invade the intestinal tissue and to favor gastrointestinal colonization. It has been recently demonstrated that SCFAs inhibit the virulence of different enteric pathogens and have protective effects against bacterial colonization. Here, we present an overview of SCFAs production by gut microbiota and their effects on the recovery of intestinal barrier integrity during infections by microorganisms that affect tight junctions. These properties make them excellent candidates in the treatment of infectious diseases that cause damage to the intestinal epithelium.

9,404 views

102 citations

Summary of CD36 on lipid uptake, de novo synthesis transport and intestinal hormone in the intestine. (1) Dietary lipids, such as triglyceride (TG) and cholesteryl esters (CE) are completely digested by pancreatic enzymes in the intestinal lumen, producing fatty acids (FAs), monoacylglycerols (MAGs), cholesterol. The uptake of FAs and MAGs into the enterocyte can be driven by the concentration gradient or facilitated by other proteins such as CD36. Cholesterol uptake is mediated by Niemann-Pick C1-like 1 (NPC1L1) protein. After being taken up by enterocytes, products of lipid digestion are re-esterified by a well-coordinated group of proteins [including acyl-CoA synthetase (ACS) and acyl-CoA:cholesterol acyltransferase (ACAT)] and assembled into TG and CE. Intestinal lipids are then packaged into pre-chylomicrons (pre-CM) with apolipoprotein A-IV (apoA-IV) and apolipoprotein B-48 (apoB-48) or stored as intracellular lipid droplets. Microsomal triglyceride transfer protein (MTP) mediates the packaging of lipids into pre-CM, which are transported from the endoplasmic reticulum to the Golgi apparatus for maturation via the pre-chylomicron transport vesicle (PCTV). Mature chylomicrons (CM) are then secreted into intestinal lymph trunk and transported by the lymphatic system into the circulation. (2) CD36 on the enteroendocrine cell (EEC) mediates the secretion of multiple intestinal hormones, including cholecystokinin (CCK), secretin, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon-like peptide-1 (GLP-2). In turn, these intestinal peptides/hormones act on their receptors on enterocytes to modulate CD36 expression and function.

Review

28 April 2021

CD36 Senses Dietary Lipids and Regulates Lipids Homeostasis in the Intestine

Lei Zhao

, 4 more and

Xiong Z. Ruan

6,999 views

29 citations

The role of free fatty acid receptor 2 (FFAR2) and hydroxycarboxylic acid receptor 2 (HCAR2) in gut homeostasis. Gut microbiota ferment dietary fibers into short-chain fatty acids (SCFAs), and these can activate their receptors expressed on intestinal epithelial cells and immune cells like neutrophils, dendritic cells (DC), and innate lymphoid cells 3 (ILC3). The activation of FFAR2 and HCAR2 in intestinal epithelial and DC promotes the secretion of interleukin (IL)-18 via inflammasome activation, and IL-10, respectively. IL-10 in turn promotes the differentiation and proliferation of T regulatory (Treg) cells that together with IL-18 protect against conditions leading to colonic inflammation and colorectal cancer. SCFAs through FFAR2 induce neutrophil chemotaxis to inflammatory sites and production of IL-1β. IL-1β engages an IL-1 receptor (IL-1R) on ILC3, promoting IL-22 production that will contribute to tissue integrity and host defense. SCFAs can also stimulate the intestinal immunoglobulin A (IgA) secretion by B cells, induced by retinoic acid (RA) production, although this mechanism is still debated.

Review

08 April 2021

Participation of Short-Chain Fatty Acids and Their Receptors in Gut Inflammation and Colon Cancer

María Daniella Carretta

, 3 more and

Rafael Agustín Burgos

Short-chain fatty acids (SCFAs) are the main metabolites produced by the bacterial fermentation of dietary fiber, and they play a critical role in the maintenance of intestinal health. SCFAs are also essential for modulating different processes, and they have anti-inflammatory properties and immunomodulatory effects. As the inflammatory process predisposes the development of cancer and promotes all stages of tumorigenesis, an antitumor effect has also been associated with SCFAs. This is strongly supported by epidemiological studies showing that a diet rich in fiber is linked to a reduced risk of colon cancer and has significant clinical benefits in patients with inflammatory bowel disease (IBD). SCFAs may signal through the metabolite-sensing G protein-coupled receptors free fatty acid receptor 3 [FFAR3 or G protein-coupled receptor 41 (GPR41)], FFAR2 (GPR43), and GPR109A (also known as hydroxycarboxylic acid receptor 2 or HCAR2) expressed in the gut epithelium and immune cells. This review summarizes the existing knowledge regarding the SCFA-mediated suppression of inflammation and carcinogenesis in IBD and colon cancer.

14,339 views

111 citations