Myeloid cell–specific serine palmitoyltransferase subunit 2 haploinsufficiency reduces murine atherosclerosis

Abstract

Serine palmitoyltransferase (SPT) is the first and rate-limiting enzyme of the de novo biosynthetic pathway of sphingomyelin (SM). Both SPT and SM have been implicated in the pathogenesis of atherosclerosis, the development of which is driven by macrophages; however, the role of SPT in macrophage-mediated atherogenesis is unknown. To address this issue, we have analyzed macrophage inflammatory responses and reverse cholesterol transport, 2 key mediators of atherogenesis, in SPT subunit 2-haploinsufficient (Sptlc2 +/-) macrophages. We found that Sptlc2 +/-macrophages have significantly lower SM levels in plasma membrane and lipid rafts. This reduction not only impaired inflammatory responses triggered by TLR4 and its downstream NF-κB and MAPK pathways, but also enhanced reverse cholesterol transport mediated by ABC transporters. LDL receptor-deficient (Ldlr -/-) mice transplanted with Sptlc2 +/-bone marrow cells exhibited significantly fewer atherosclerotic lesions after high-fat and high-cholesterol diet feeding. Additionally, Ldlr -/-mice with myeloid cell-specific Sptlc2 haploinsufficiency exhibited significantly less atherosclerosis than controls. These findings suggest that SPT could be a novel therapeutic target in atherosclerosis.

Tristetraprolin Limits Inflammatory Cytokine Production in Tumor-Associated Macrophages in an mRNA Decay–Independent Manner

“…5D). Second, when we genetically eliminated p38α in macrophages with the LysM-Cre deleter (p38α ΔM ) as previously reported (30), we observed negligible depletion of p38α amounts, arguing conclusions drawn using this deleter system are difficult to interpret (Fig. 5E,F).…”

Sphingomyelin Depletion Impairs Anionic Phospholipid Inward Translocation and Induces Cholesterol Efflux

“…In SM-depleted mutant CHO cells, ABCA1-mediated cholesterol efflux was increased without altering the cell surface or total ABCA1 levels (50). Also, a genetic lowering of macrophage SM via a different subunit of serine palmitoyltransferease (Sptlc2-hemizygous mice) was also reported to increase the ABCA1-dependent cholesterol efflux to apoAI in cholesterol-loaded cells, associated with a decrease in SPT1 protein and an increase in total ABCA1 protein levels (51). Meanwhile Ghering and Davidson (40) reported that the addition of a short chain ceramide analog to ABCA1 expressing cells increases ABCA1 levels and cholesterol efflux to apoAI, whereas physiological ceramides had no effect.…”

Macrophage Phenotype and Function in Different Stages of Atherosclerosis

“…One of the ACSL isoforms expressed in macrophages, ACSL1, is markedly upregulated by inflammatory mediators and is required for atherosclerosis in diabetic mice 64 . Moreover, macrophages deficient in serine palmitoyltransferase subunit 2 (SPT) exhibit reduced levels of sphingomyelin in lipid rafts, which results in reduced TLR4 activity and reduced atherosclerosis 65 . Fatty acids might promote inflammatory processes by several different mechanisms, including altered activation of nuclear receptors, altered generation of bioactive lipid mediators, and facilitation of TLR4 activation through organization of TLR4 receptor complexes within lipid raft domains.…”