Insulin-induced lipid body accumulation is accompanied by lipid remodelling in model mast cells复制标题

胰岛素诱导的脂质体蓄积伴随着模型肥大细胞的脂质重塑

Metabolic syndrome is associated with a chronic state of hyperinsulinemia, prior to the onset of Type 2 Diabetes mellitus. Chronic insulin elevation has functional consequences for numerous cells, tissues and organs in the body, including those of the immune system. We have previously shown that chronic insulin elevation alters mast cell functional phenotypes in vitro, and there is in vivo and clinical evidence that altered levels of insulin affect the outcomes of allergic and anaphylactic inflammatory responses. Chronic insulin exposure quantitatively alters the lipid content of mast cells, causes a steatosis-like accumulation of lipid bodies similar to that observed in neutrophils and macrophages under conditions of infection. However, qualitative changes in the cellular profiles of bioactive lipids and their precursors have not been extensively explored. This is an important question arising from the marked effects that lipid remodelling has upon the net pro-and anti-inflammatory capacity of cells such as mast cells. Most lipid mediators that been shown to regulate inflammation are derived from omega-6 (n-6) or omega3 (n-3) fatty acids. These mediators include arachidonic acid (AA; 20:4n-6), linoleic acid (LA; 18:2n6), eicosapentaenoic acid (EPA; 20:5n-3), and docosahexaenoic acid (DHA; 22:6n-3). Oxidation catalyzed by cyclooxygenases, lipoxygenases, or cytochrome P450 forms the bioactive metabolite from these precursors. Acute changes in cellular status have been shown to remodel key lipid populations in mast cells and other immune cells, changing the outcome of mast cell activation and in some cases switching the cell between a pro-inflammation and a pro-resolution phenotype. Several studies have evaluated the location of the bioactive lipid precursor AA in mast cells, evaluating distribution between membrane phospholipid (phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS)) and free fatty acid (FFA) forms of AA. The distribution within these pools changes in response to mast cell activation in response to both calcium ionophore and FcεRI stimulation. These changes are functionally important as the location of the AA changes its proximity and availability to phospholipases that are concomitantly activated and catalyse pathways leading to synthesis of prostaglandins, leukotrienes, thromboxanes, HETEs, resolvins and endocannabinoids. Similarly, functional importance is ascribed to the ratios between omega-3 and omega-6-fatty acids and the abundance of DHA and EPA pools. These are precursors for inflammation resolving factors (protectins, resolvins, and maresins). Since n-6 and n-3 fatty acids are generally regarded as pro-inflammatory, and anti-inflammatory, respectively, the cellular abundance of these forms in mast cells has consequences for tissue inflammatory responses.

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