Myeloid cell–specific serine palmitoyltransferase subunit 2 haploinsufficiency reduces murine atherosclerosis
Mahua Chakraborty, Caixia Lou, Chongmin Huan, Ming-Shang Kuo, Tae-Sik Park, Guoqing Cao, Xian-Cheng Jiang
Mahua Chakraborty, Caixia Lou, Chongmin Huan, Ming-Shang Kuo, Tae-Sik Park, Guoqing Cao, Xian-Cheng Jiang
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Research Article Cardiology

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.

Authors

Mahua Chakraborty, Caixia Lou, Chongmin Huan, Ming-Shang Kuo, Tae-Sik Park, Guoqing Cao, Xian-Cheng Jiang

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Figure 6

Sptlc2+/– macrophages attenuate LPS- or palmitate-mediated expression of proinflammatory genes downstream of NF-κB and MAPKs.

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Sptlc2+/– macrophages attenuate LPS- or palmitate-mediated expression o...
(A and B) Real-time PCR for Tnfa and Il6 mRNA after treatment with (A) 1 μg/ml LPS for 15 minutes or (B) 500 μM palmitate for 30 minutes. (C) TNF-α secreted by macrophages in culture medium after treatment with 10 ng/ml LPS or 50 μM palmitate for 16 hours. (D) Mouse plasma TNF-α and IL-6 concentration after 8 hours of LPS challenge (50 μg/kg body weight i.p.). (E) Effect of exogenous SM on lysenin-mediated cell mortality. (F) Effect of exogenous SM on macrophage IL-6 secretion in response to treatment with 10 ng/ml LPS for 16 hours. Extracellular culture medium IL-6 was measured by ELISA. Data are representative of 3 independent experiments (n = 3). For in vivo studies, n = 7. *P < 0.05.