Research ArticleAtherosclerosis

Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation

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Science Translational Medicine  28 Sep 2016:
Vol. 8, Issue 358, pp. 358ra126
DOI: 10.1126/scitranslmed.aaf9087

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Artery-saving fat

Although fatty foods often have a bad reputation when it comes to atherosclerosis, a study by Çimen et al. identifies a type of fat that is not only harmless but also protective. Palmitoleate is a lipid that can be produced directly by the human body and is also found in a variety of foods, but only in small amounts. Using human cells and mouse models, the authors demonstrate that palmitoleate reduces metabolic stress in a variety of tissues as well as in atherosclerotic plaques and thus decreases the severity of atherosclerosis in mouse models.

Abstract

De novo lipogenesis (DNL), the conversion of glucose and other substrates to lipids, is often associated with ectopic lipid accumulation, metabolic stress, and insulin resistance, especially in the liver. However, organ-specific DNL can also generate distinct lipids with beneficial metabolic bioactivity, prompting a great interest in their use for the treatment of metabolic diseases. Palmitoleate (PAO), one such bioactive lipid, regulates lipid metabolism in liver and improves glucose utilization in skeletal muscle when it is generated de novo from the obese adipose tissue. We show that PAO treatment evokes an overall lipidomic remodeling of the endoplasmic reticulum (ER) membranes in macrophages and mouse tissues, which is associated with resistance of the ER to hyperlipidemic stress. By preventing ER stress, PAO blocks lipid-induced inflammasome activation in mouse and human macrophages. Chronic PAO supplementation also lowers systemic interleukin-1β (IL-1β) and IL-18 concentrations in vivo in hyperlipidemic mice. Moreover, PAO prevents macrophage ER stress and IL-1β production in atherosclerotic plaques in vivo, resulting in a marked reduction in plaque macrophages and protection against atherosclerosis in mice. These findings demonstrate that oral supplementation with a product of DNL such as PAO can promote membrane remodeling associated with metabolic resilience of intracellular organelles to lipid stress and limit the progression of atherosclerosis. These findings support therapeutic PAO supplementation as a potential preventive approach against complex metabolic and inflammatory diseases such as atherosclerosis, which warrants further studies in humans.

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