Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment

The term “lipid” is used to identify a large set of hydrophobic and amphiphilic molecules such as free fatty acids, sterols, fatty acid esters, and phospholipids.These molecules are involved in forming fundamental structures in cells and tissues, providing energy for the metabolic needs of organisms, and regulating several homeostatic processes within and outside of cells, including organelle homeostasis, immune function, inter-organ communication, energy metabolism, and cell survival.However, when the balance in their metabolism and composition is altered by environmental or metabolic stress, lifestyle, and genetic or epigenetic factors, lipids can also become critical components of pathophysiological cascades that are detrimental to healthy cell and tissue function.Hence, although lipids play fundamental physiological roles, in excess or in improper composition, they can be highly damaging, leading to organelle dysfunction, cell death, chronic inflammation, and disturbances in energy and substrate metabolism and survival responses.In this review, we primarily focus on the roles of lipid classes that regulate immune responses and signaling mechanisms, which perpetuate a vicious cycle of metabolic and inflammatory disturbances leading to disease.Abstract Lipids encompass a wide variety of molecules such as fatty acids, sterols, phospholipids, and triglycerides.These molecules represent a highly efficient energy resource and can act as structural elements of membranes or as signaling molecules that regulate metabolic homeostasis through many mechanisms.Cells possess an integrated set of response systems to adapt to stresses such as those imposed by nutrient fluctuations during feeding-fasting cycles.While lipids are pivotal for these homeostatic processes, they can also contribute to detrimental metabolic outcomes.When metabolic stress becomes chronic and adaptive mechanisms are overwhelmed, as occurs during prolonged nutrient excess or obesity, lipid influx can exceed the adipose tissue storage capacity and result in accumulation of harmful lipid species at ectopic sites such as liver and muscle.As lipid metabolism and immune responses are highly integrated, accumulation of harmful lipids or generation of signaling intermediates can interfere with immune regulation in multiple tissues, causing a vicious cycle of immune-metabolic dysregulation.In this review, we summarize the role of lipotoxicity in metaflammation at the molecular and tissue level, describe the significance of anti-inflammatory lipids in metabolic homeostasis, and discuss the potential of therapeutic approaches targeting pathways at the intersection of lipid metabolism and immune function.-ErikciErtunc, M., and G. S. Hotamisligil.Lipid signaling and lipotoxicity in metaflammation: indications for metabolic disease pathogenesis and treatment.J. Lipid Res.