Lipids play an important role in cellular inflammation and research has identified a role for a number of dietary and endogenously produced fatty acids in the generation or inhibition of systemic inflammation. For example, the long chain polyunsaturated fatty acids (PUFA) eicosapentanoic acid (EPA, C20:5 (n-3)) and docosahexanoic acid (DHA, C22:5 (n-3)) are incorporated into cell membranes where they are metabolised to anti-inflammatory prostaglandins and leukotrienes that help inhibit the pro-inflammatory effects of arachidonic acid (AA, C20:4 (n-3)) derived eicosanoids. In addition, the linoleic acid (LA, C18:2 (n-6)) metabolite, dihomo-γ-linolenic acid (DGLA, C18:3 n-6)) is metabolised to prostaglandins that can have a strong anti-inflammatory effect. Saturated fatty acids (SFA) too play an important role in generating cellular inflammation, and in particular the saturated fatty acids derived from de novo lipogenesis are now understood to have important implications for inflammatory responses by immune cells.
Evidence suggests that SFA may act directly as ligands for receptors on the surface of immune cells, and promote inflammation. In addition, the fatty acids may be transported into the cells where they are metabolised to a number of lipid substances such as diacylglycerols and ceremides which are both potent inflammatory substances. The accumulation of white adipose tissue is known to cause macrophage infiltration and the release of cytokines that result in systemic inflammation. Ingestion of large quantities of fructose causes an increase in unregulated de novo lipogenesis and the resultant fatty acids are exported to the peripheral tissues where they may interfere with the sensitivity of the insulin receptor. As insulin resistance develops a number of metabolic changes results in the metabolic syndrome, which is characterised by abdominal obesity and blood lipid changes, which if untreated can ultimately lead to diabetes and cardiovascular disease.
Both dietary SFA and those derived from de novo lipogenesis therefore play an important role in determining the inflammatory status of the individual. However the fate of these SFA is not fixed because desaturating enzymes exist that can alter their structure by the incorporation of a double bond. Intracellulular levels of monounsaturated fatty acids (MUFA) are controlled by the enzyme stearoyl-CoA desaturase which incorporates a double bond into the ∆9 position of the hydrocarbon chain. Steroyl-CoA desaturase is attached to the membrane of the endoplasmic reticulum and can use both dietary or endogenously produced saturated fatty acids as a substrate to produce MUFA. Two isoforms exist in humans designated SCD1 and SCD2. Steroyl-CoA desaturase is found predominately in adipose tissue and liver and its activity is induced by a glucose, fructose, high carbohydrate diets cholesterol and vitamins A and D, and inhibited by n-3 and n-6 PUFA.
Steroyl-CoA desaturase therefore is the key enzyme that regulates the ratio of stearic acid (SA, C18:0) to oleic acid (OA, C18:1 (n-9)) in cells. This ratio has a regulatory effect on a number of aspect of cell growth, differentiation and regulation of cellular metabolism. For example, genetic deficiency of SDC1 protects against obesity in mice and reducing expression of SCD1 causes favourable weight changes and metabolic outcomes including improved insulin sensitivity. However, SDC1 deficiency in β-cells of the pancreas may cause metabolic dysfunction because β-cells are highly sensitive to the toxic effects of SFA and SCD1 is able to convert the SFA to MUFA which protects the cells. Reduced expression of SCD1 may also be associated with a reduction in cancer cell growth because cancer cells may be susceptible to changes in the ratio of stearic acid to oleic acid which may affect cell growth and differentiation process.
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