title: Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes.
abstract: Free fatty acids (FFAs) are metabolic intermediates that may be obtained through the diet or synthesized endogenously. In addition to serving as an important source of energy, they produce a variety of both beneficial and detrimental effects. They play essential roles as structural components of all cell membranes and as signaling molecules regulating metabolic pathways through binding to nuclear or membrane receptors. However, under conditions of FFAs overload, they become toxic, inducing ROS production, ER stress, apoptosis and inflammation. SFAs (saturated fatty acids), unlike UFAs (unsaturated fatty acids), have recently been proposed as triggers of the NLRP3 inflammasome, a molecular platform mediating the processing of IL-1β in response to infection and stress conditions. Interestingly, UFAs, especially ω-3 FAs, inhibit NLRP3 inflammasome activation in various settings. We focus on emerging models of NLRP3 inflammasome activation with a special emphasis on the molecular mechanisms by which FFAs modulate the activation of this complex. Taking into consideration the current literature and FFA properties, we discuss the putative involvement of mitochondria and the role of cardiolipin, a mitochondrial phospholipid, proposed to be sensed by NLRP3 after release, exposure and/or oxidation. Finally, we review how this SFA-mediated NLRP3 inflammasome activation contributes to the development of both insulin resistance and deficiency associated with obesity/type 2 diabetes. In this context, we highlight the potential clinical use of ω-3 FAs as anti-inflammatory compounds.
authors.affiliation: University of Liege, GIGA-Signal Transduction, Laboratory of Virology and Immunology, Liege 4000, Belgium. Electronic address: S.Legrand@ulg.ac.be.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Legrand-Poels
authors.affiliation: University of Liege, GIGA-Signal Transduction, Laboratory of Virology and Immunology, Liege 4000, Belgium; University of Liege Hospital, Division of Diabetes, Nutrition, and Metabolic Disorders, Liege 4000, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Esser
authors.affiliation: University of Liege, GIGA-Signal Transduction, Laboratory of Virology and Immunology, Liege 4000, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: L'homme
authors.affiliation: University of Liege Hospital, Division of Diabetes, Nutrition, and Metabolic Disorders, Liege 4000, Belgium.
authors.forename: André
authors.initials: A
authors.lastname: Scheen
authors.affiliation: University of Liege Hospital, Division of Diabetes, Nutrition, and Metabolic Disorders, Liege 4000, Belgium.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Paquot
authors.affiliation: University of Liege, GIGA-Signal Transduction, Laboratory of Virology and Immunology, Liege 4000, Belgium.
authors.forename: Jacques
authors.initials: J
authors.lastname: Piette
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects; D007333:Insulin Resistance / Q000502:physiology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009765:Obesity / Q000235:genetics / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D005230:Fatty Acids, Nonesterified; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human
keywords: Free fatty acids; Inflammation; Insulin resistance; Metabolic stress; NLRP3 inflammasome; Type 2 diabetes