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Introduction

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High-Yield Terms

  • Oleoylethanolamide: amide derivative of oleic acid synthesized by intestinal cells following intake in the diet, functions by binding to the fat-sensing receptor, GPR119

  • Lysophospholipid: represents a class of phospholipid generated via the removal of the fatty acid esterified to the sn1 or sn2 position of the glycerol backbone catalyzed by either PLA1 or PLA2, respectively

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Bioactive Lipids and Lipid-Sensing Receptors

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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.

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Fatty Acids and Fatty Acid–Sensing GPCRs

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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).

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  • 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 ...

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