Bioactive Lipids and Lipid-Sensing Receptors

Until recently fats were considered mere sources of energy and as components of biological membranes. However, research over the past 10 to 15 years has demonstrated a widely diverse array of biological activities associated with fatty acids and fatty acid derivatives as well as other lipid compounds. Bioactive lipids span the gamut of structural entities from simple saturated fatty acids to complex molecules such as those derived from various omega-3 and omega-6 fatty acids and those derived from sphingosine. All bioactive lipids exert their effects through binding to specific receptors of the G-protein–coupled receptor (GPCR) family. Bioactive lipids play important roles in energy homeostasis, cell proliferation, metabolic homeostasis, and regulation of inflammatory processes.

Fatty Acids and Fatty Acid–Sensing GPCRs

Several novel GPCRs have been identified in recent years that have been shown to bind and be activated by free fatty acids and/or lipid molecules. Three tandemly encoded intronless genes on chromosome 19 were originally identified as GPR40 (later also identified as free fatty acid receptor 1 [FFAR1]), GPR41 (FFAR3), and GPR43 (FFAR2). Subsequent to their isolation and characterization GPR40 was shown to bind and be activated by medium- and long-chain free fatty acids, whereas, GPR41 and GPR43 were shown to be activated by short-chain free fatty acids. GPR84 was identified as an orphan GPCR in a screen of differentially expressed genes in granulocytes. GPR119 and GPR120 were identified as a result of the human genome sequencing project and shown to be members of the rhodopsin-like family of GPCR (see Chapter 40).

     GPR34: GPR34 belongs to the P2Y family of GPCRs to which other emerging newly identified lysophospholipid receptors, such as LPA₄/P2Y9/GPR23, LPA₅/GPR92, and LPA₆/P2Y5 belong. The natural ligand for GPR34 has recently been determined to be lysophosphatidylserine (lysoPS) which is the product of the action of phosphatidylserine (PS)-specific PLA₁ (PS-PLA₁) described below.

     GPR35: GPR35 was first described to be activated by kynurenic acid (an intermediate in tryptophan catabolism that has neurotransmitter activity as an antiexcitotoxic and anticonvulsant) but is most likely the receptor for 2-arachidonyl lysophosphatidic acid (LPA). The emerging function of GPR35 demonstrates that it may be an important target involved in pain, heart disease, inflammatory bowel disease (IBD), cancer, and asthma. Expression of GPR35 is seen at highest levels in the stomach, small intestine, and colon. Expression, albeit at lower levels than in the GI, are seen in lung, uterus, spinal cord, and several types of white cells including basophils, eosinophils, mast cells peripheral monocytes, and macrophages.

     GPR40: GPR40 is abundantly expressed in pancreatic β-cells and is also found in the gut in enteroendocrine cells. The preferred ligands for GPR40 are medium- to long-chain saturated fatty acids (C12-C16) as well as unsaturated fatty acids (C18-C22). GPR40 is coupled to a G_q protein that activates PLCβ upon ligand binding to the receptor. The activation of GPR40 in pancreatic β-cells results in increased cytosolic Ca²⁺ via IP₃-mediated release from the endoplasmic reticulum. The increased cytosolic Ca²⁺ can depolarize the β-cell leading to an influx of additional Ca²⁺ leading to increased secretion of insulin. This is an important mechanism by which fatty acids enhance glucose-stimulated insulin secretion (GSIS). A synthetic agonist for GPR40 is currently being tested as a potentially useful orally active antidiabetic drug.

     GPR41 and GPR43: GPR41 and GPR43 are activated by short-chain fatty acids (SCFAs) such as propionic acid, butyric acid, and pentanoic acid. Both of these receptors are expressed at highest levels in adipose tissue and immune cells but are also found expressed in enteroendocrine cells of the gut. The activation of GPR41 and GPR43 is involved in adipogenesis and the production of leptin by adipose tissue. In the gut, GPR41 and GPR43 are involved in responses to SCFAs derived from gut microbiota metabolism of complex carbohydrates. Intestinal GPR41 plays a critical role in energy homeostasis and as well as control of feeding behaviors through the activated release of gut hormones such as PYY.

     GPR55: GPR55 is a member of the rhodopsin-like family of GPCRs. Expression of GPR55 is highest in brain, GI system, adrenal glands, testis, endothelial cells, and numerous cancers. GPR55 was initially suggested to be a cannabinoid receptor for cannabinoid and endocannabinoid responses that are not mediated by the classical cannabinoid receptors: CB₁ and CB₂. Despite the fact that certain endocannabinoids, phytocannabinoids, and synthetic cannabinoids can act as GPR55 agonists or antagonists, the most potent GPR55 agonist characterized to date is 2-arachidonoyl lysophosphatidylinositol (LPI).

     GPR84: GPR84 was originally shown to be activated by lipopolysaccharide (LPS) suggesting that medium-chain free fatty acids could be regulating inflammatory responses via interaction with GPR84. Subsequently it was demonstrated that GPR84 is a receptor for medium-chain free fatty acids such as capric acid (C10:0), undecenoic acid (C11:0), and lauric acid (C12:0). GPR84 is highly expressed in leukocytes.

     GPR119: GPR119 is expressed at the highest levels in the pancreas and fetal liver with expression also seen in the GI tract, specifically the ileum and colon. GPR119 is a member of the class A family (rhodopsin-type) of GPCRs. GPR119 binds to long-chain fatty acids including oleoylethanolamide (OEA), lysophosphatidylcholine (LPC), various lipid amides, and retinoic acid. The role of GPR119 in metabolic homeostasis is described in more detail below in the section Oleoylethanolamide.

GPR120: Obesity and Diabetes

GPR120 is specifically activated by long-chain nonesterified fatty acids (NEFA), in particular in the intestines by α-linolenic acid (ALA). Activation of GPR120 in the intestines results in increased glucagon-like peptide 1 (GLP-1) secretion from enteroendocrine L cells (see Chapter 44). GPR120 is highly expressed in adipose tissue and pro-inflammatory macrophages. In contrast, negligible expression of GPR120 is seen in muscle, pancreatic β-cells, and hepatocytes. However, GPR120 is highly inducible in liver resident macrophage-like cells known as Kupffer cells.

Short-chain fatty acids are known to be pro-inflammatory and unsaturated fatty acids are generally neutral. In contrast the omega-3 polyunsaturated fatty acid(PUFA), DHA, and EPA exert potent anti-inflammatory effects through GPR120. The anti-inflammatory effects DHA and EPA activation of GPR120 are due to inhibition of both the Toll-like receptor (TLR) and tumor necrosis factor-α (TNF-α) inflammatory signaling pathways (Figure 23-1). The TLRs are a class of noncatalytically active transmembrane receptors that are involved in mediating responses of the innate immune system.

DHA stimulation of GPR120 is also involved in glucose homeostasis in adipose tissue due to increased GLUT4 translocation to the cell surface with a subsequent increase in glucose transport into the cells. The effects of DHA on glucose uptake in adipocytes are additive to those of insulin. Although it is possible to propose that the insulin-sensitizing effects of omega-3 PUFAs in adipocytes contribute to the overall insulin-sensitizing actions of these fatty acids, muscle glucose uptake accounts for the great majority of insulin-stimulated glucose disposal but GPR120 is not expressed in muscle. Since chronic, low-grade tissue inflammation is an important cause of obesity-related insulin resistance, the anti-inflammatory effects of GPR120 stimulation are likely coupled to insulin-sensitizing actions.

Oleoylethanolamide

Oleoylethanolamide (OEA, Figure 23-2) is a member of the fatty-acid ethanolamide family that includes palmitoylethanolamide (PEA) and N-arachidonylethanolamide (anandamide). Anandamide is an endogenous ligand (endocannabinoid) for the cannabinoid receptors. OEA is produced by mucosal cells in the proximal small intestine from dietary oleic acid. Synthesis of OEA occurs on demand within the membrane of the intestinal mucosal cell by 2 concerted reactions. Metabolism of OEA occurs via hydrolysis to oleic acid and ethanolamine. Two enzymes are known to be responsible for OEA hydrolysis.

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