Meta-Biol

• Pathways

Maresin-like mediators MaR-L1, Mar-L2 and 14,21-dihydroxy docosahexaenoic acids are normally synthesized by leukocytes, platelets and macrophages, via the pathways described here. Impaired production of these specialised proresolving mediators (SPMs) in diabetic skin wounds is associated with impaired macrophage function and delayed or absent wound healing (Brem & Tomic-Canic 2007, Boniakowski et al 2017). Macrophages play critical roles in wound healing by mechanisms as yet unknown. They are active in both the initiation (M1 macrophage phenotype) and the resolution (M2 macrophage phenotype) of inflammatory processes. In a pathological state, the switch from the M1 phenotype macrophage to the M2 phenotype macrophage may be delayed or fail to occur, which can result in chronic low-grade inflammation. This macrophage phenotype skewing toward an inflammatory phenotype has been implicated in the pathogenesis of type 2 diabetes (T2D) and the non-healing of diabetic wounds (Boniakowski et al 2017, Pradhan et al. 2009).

Administration of maresin-like SPMs to diabetic mice with induced wounds have been shown to act as autocrine/paracrine factors in restoring reparative functions of macrophages (Hong et al. 2014, Tian et al. 2011a, 2011b, Lu et al. 2010, Hellman et al. 2012).

Lipids are hydrophobic but otherwise chemically diverse molecules that play a wide variety of roles in human biology. They include ketone bodies, fatty acids, triacylglycerols, phospholipids and sphingolipids, eicosanoids, cholesterol, bile salts, steroid hormones, and fat-soluble vitamins. They function as a major source of energy (fatty acids, triacylglycerols, and ketone bodies), are major constituents of cell membranes (cholesterol and phospholipids), play a major role in their own digestion and uptake (bile salts), and participate in numerous signaling and regulatory processes (steroid hormones, eicosanoids, phosphatidylinositols, and sphingolipids) (Vance & Vance 2008 - URL).

The central steroid in human biology is cholesterol, obtained from animal fats consumed in the diet or synthesized de novo from acetyl-coenzyme A. (Vegetable fats contain various sterols but no cholesterol.) Cholesterol is an essential constituent of lipid bilayer membranes and is the starting point for the biosyntheses of bile acids and salts, steroid hormones, and vitamin D. Bile acids and salts are mostly synthesized in the liver. They are released into the intestine and function as detergents to solubilize dietary fats. Steroid hormones are mostly synthesized in the adrenal gland and gonads. They regulate energy metabolism and stress responses (glucocorticoids), salt balance (mineralocorticoids), and sexual development and function (androgens and estrogens). At the same time, chronically elevated cholesterol levels in the body are associated with the formation of atherosclerotic lesions and hence increased risk of heart attacks and strokes. The human body lacks a mechanism for degrading excess cholesterol, although an appreciable amount is lost daily in the form of bile salts and acids that escape recycling.

Aspects of lipid metabolism currently annotated in Reactome include lipid digestion, mobilization, and transport; fatty acid, triacylglycerol, and ketone body metabolism; peroxisomal lipid metabolism; phospholipid and sphingolipid metabolism; cholesterol biosynthesis; bile acid and bile salt metabolism; and steroid hormone biosynthesis.

Metabolic processes in human cells generate energy through the oxidation of molecules consumed in the diet and mediate the synthesis of diverse essential molecules not taken in the diet as well as the inactivation and elimination of toxic ones generated endogenously or present in the extracellular environment. The processes of energy metabolism can be classified into two groups according to whether they involve carbohydrate-derived or lipid-derived molecules, and within each group it is useful to distinguish processes that mediate the breakdown and oxidation of these molecules to yield energy from ones that mediate their synthesis and storage as internal energy reserves. Synthetic reactions are conveniently grouped by the chemical nature of the end products, such as nucleotides, amino acids and related molecules, and porphyrins. Detoxification reactions (biological oxidations) are likewise conveniently classified by the chemical nature of the toxin.

At the same time, all of these processes are tightly integrated. Intermediates in reactions of energy generation are starting materials for biosyntheses of amino acids and other compounds, broad-specificity oxidoreductase enzymes can be involved in both detoxification reactions and biosyntheses, and hormone-mediated signaling processes function to coordinate the operation of energy-generating and energy-storing reactions and to couple these to other biosynthetic processes.