Editors' ChoiceAtherosclerosis

SORTing out lipid handling in atherosclerosis

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Science Translational Medicine  28 Jan 2015:
Vol. 7, Issue 272, pp. 272ec17
DOI: 10.1126/scitranslmed.aaa5554

An abnormal amount of lipids (dyslipidemia) and inflammation are risk factors for the development of atherosclerosis—the build-up of hard, fatty deposits in arteries. However, the direct mechanisms linking dyslipidemia with inflammation in atherogenesis remain elusive. Clinical genetics studies have identified SORT1, the gene that encodes sortilin, as a contributor to LDL cholesterol levels and the risk of atherosclerosis in humans. Furthermore, SORT1 gene expression has been detected in macrophages, but the function is unknown. In a new study, Patel et al. establish sortilin’s role in macrophages as a mediator of LDL cholesterol uptake, foam cell formation, and a major contributor to atherogenesis.

The authors used mouse models to establish sortilin’s macrophage-specific effects. Initially, the authors examined the effects of sortilin deficiency in mice with a humanized form of dyslipidemia. Sortilin deficiency dramatically reduced atherogenesis while having no effects on plasma cholesterol. Next, the authors confirmed that macrophage sortilin deficiency was responsible for the decrease in atherogenesis by transplanting the bone marrow of mice lacking Sort1 and/or the Ldl receptor into atherosclerosis-prone Ldlr-/- mice. The mice that received the cell transplant from Sort1/Ldlr-/- mice demonstrated a 69% reduction in aortic atherosclerotic lesions and a 34% reduction in aortic root lesion area while having no effects on plasma LDL cholesterol. To suggest a possible mechanism for the effect of sortilin deficiency on the role of macrophages in atherogenesis, Patel et al. looked at macrophages from both peritoneal and hematopoietic lineages and found that sortilin deficiency in both lineages decreased LDL cholesterol uptake while having no effect on additional macrophage properties.

In summary, this study suggests that macrophage sortilin deficiency protects against atherosclerosis by reducing macrophage LDL uptake, foam cell formation, and atherogenesis. Although performed only in animals, this study identifies sortilin signaling in macrophages as a potential therapeutic target in the battle against atherosclerosis.

K. Patel et al., Macrophage sortilin promotes LDL uptake, foam cell formation, and atherosclerosis. Circ. Res. 10.1161/CIRCRESAHA.116.305811 (2015). [Abstract]

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