Stearoyl-CoA desaturase-1 impairs the reparative properties of macrophages and microglia in the brain

Abstract

Failure of remyelination underlies the progressive nature of demyelinating diseases such as multiple sclerosis. Macrophages and microglia are crucially involved in the formation and repair of demyelinated lesions. Here we show that myelin uptake temporarily skewed these phagocytes toward a disease-resolving phenotype, while sustained intracellular accumulation of myelin induced a lesion-promoting phenotype. This phenotypic shift was controlled by stearoyl-CoA desaturase-1 (SCD1), an enzyme responsible for the desaturation of saturated fatty acids. Monounsaturated fatty acids generated by SCD1 reduced the surface abundance of the cholesterol efflux transporter ABCA1, which in turn promoted lipid accumulation and induced an inflammatory phagocyte phenotype. Pharmacological inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo. These findings identify SCD1 as a novel therapeutic target to promote remyelination.

Genome-Wide Transcriptomic Analysis Identifies Pathways Regulated by Sterculic Acid in Retinal Pigmented Epithelium Cells

“…SCD over-expression has been detected in many cancer types and it is related to increased cell proliferation, reduction of relapse-free survival and poor prognosis in patients [42] while its chemical inhibition, or gene silencing, reduces tumoral resistance and activates cell death pathways in many cancer cell lines [42]. Recently, it has been described that SCD1 inhibition promotes remyelination because, in macrophages, SCD1 controls cholesterol efflux transporters (ABCA1), increasing lipid accumulation and promoting a proinflammatory phenotype [43].…”

Metabolic Control of Smoldering Neuroinflammation

“…Indeed, recent transcriptomics studies have provided indirect evidence supporting drastic changes in the lipid metabolism of activated microglia, as seen by the upregulation of lipid metabolism genes such as Trem2, Apoe, Spp1, Cts7, Lpl , and Fabp5 under inflammatory conditions ( 30 , 70 , 74 , 75 ). However, the role of these genes and pathways is still under investigation, especially in diseases where myelin deposition in the CNS parenchyma can exceed the lipid processing capacity of myeloid cells ( Figure 2 ) ( 73 , 76 , 77 ).…”

Stearoyl-CoA Desaturase-2 in Murine Development, Metabolism, and Disease

“…These data suggest that SCD2 is a critically important enzyme that controls the supply of nervonoyl-CoA (C24:1n9) for myelin biosynthesis and that inhibition of SCD2 may significantly contribute to MS [46]. In contrast, SCD1 inhibition or phagocyte-specific deficiency of Scd1 accelerated remyelination ex vivo and in vivo [59]. Future research is needed to determine the cell-specific roles of SCD1 and SCD2 in MS.…”