Liberating Chiral Lipid Mediators, Inflammatory Enzymes, and LIPID MAPS from Biological Grease

Abstract

In 1970, it was well accepted that the central role of lipids was in energy storage and metabolism, and it was assumed that amphipathic lipids simply served a passive structural role as the backbone of biological membranes. As a result, the scientific community was focused on nucleic acids, proteins, and carbohydrates as information-containing molecules. It took considerable effort until scientists accepted that lipids also "encode" specific and unique biological information and play a central role in cell signaling. Along with this realization came the recognition that the enzymes that act on lipid substrates residing in or on membranes and micelles must also have important signaling roles, spurring curiosity into their potentially unique modes of action differing from those acting on water-soluble substrates. This led to the creation of the concept of "surface dilution kinetics" for describing the mechanism of enzymes acting on lipid substrates, as well as the demonstration that lipid enzymes such as phospholipase A 2 (PLA 2 ) contain allosteric activator sites for specific phospholipids as well as for membranes. As our understanding of phospholipases advanced, so did the understanding that many of the lipids released by these enzymes are chiral informationcontaining signaling molecules; for example, PLA 2 regulates the generation of precursors for the biosynthesis of eicosanoids and other bioactive lipid mediators of inflammation and resolution underlying disease progression. The creation of the LIPID MAPS initiative in 2003 and the ensuing development of the lipidomics field have revealed that lipid metabolites are central to human metabolism. Today lipids are recognized as key mediators of health and disease as we enter a new era of biomarkers and personalized medicine. This article is my personal "reflection" on these scientific advances.

Omega-6 fatty acids and inflammation

“…Phospholipase A2 is activated by many inflammatory stimuli and acts to cleave ARA from the sn-2 position of cell membrane phospholipids, particularly phosphatidylcholine [24]. The ARA that is released acts as a substrate for cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 enzymes to form eicosanoid mediators [25][26][27].…”

Autofluorescence‐based optical biopsy: An effective diagnostic tool in hepatology

“…To date, fluorescent lipids have been considered as mere fraction of overall liver tissue emission, relatable to fat accumulation . A step forward in the diagnostic meaning of fluorescing lipids has been promoted by 2 factors: the identification of some free fatty acids, such as arachidonic, linoleic and linolenic acids, accounting for the fluorescing lipid fraction, and the growing evidence of their roles as precursors of regulating agents of complex, protective or injuring pathways activated by hazardous stimuli . For example, prevailing anti‐inflammatory effects have been suggested for α‐linolenic acid, precursors of eicosapentaenoic acid and docosahexaenoic acid.…”

“…64,123 These findings open up important diagnostic perspectives as regards directly estimating directly the balance between AA and the miscellanea of the other FFAs, for a direct, sensitive detection of their mobilization from cell membranes or storehouses as precursors of agents regulating harmful or protective responses to hazardous stimuli. [65][66][67][68][69][70][71] Possible applications include the monitoring of oxidative events in fatty livers relevant to the risk of progression to more severe liver and extrahepatic diseases. 67,68,[124][125][126][127][128][129] With regard to bilirubin, besides investigations on molecule photoisomerization to cure hyperbilirubinemia toxicity, 61,85,130 studies on its bichromophore properties have improved its diagnostic meaning in the bile.…”

“…The procedure was found to be efficient in differentiating between nonalcoholic fatty liver disease and chronic hepatitis, 142 at least in partial dependence on the release of components of the extracellular matrix into circulation from liver undergoing fibrosis. 143 Considering that fatty acids are recognized agents in sensing cell responses to hazardous stimuli, and that polyunsaturated fatty acids and their metabolites have been proposed as blood biomarkers of liver disease progression, [65][66][67][68][69][70][71]144 an additional diagnostic possibility is adapting the detection of the AF of free FFAs from liver tissue extracts to serum analysis, in a sort of liquid optical biopsy. 145…”

“…Fluorescing forms of reduced NAD(P)H and oxidized flavins are indicated by star frames. Reproduced and modified with permission, from Croce and Bottiroli (2017) of complex, protective or injuring pathways activated by hazardous stimuli 65,66. For example, prevailing antiinflammatory effects have been suggested for α-linolenic acid, precursors of eicosapentaenoic acid and docosahexaenoic acid.Prevailing pro-inflammatory effects are ascribed to linoleic acids, and its derivatives γ-linolenic acid, arachidonic acid (AA) and an ensuing group of oxygenated products, called eicosanoids.…”