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autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Nat. Comms. 8, 15750 (2017) The development of atherosclerotic plaques is characterized by progressive macrophage autophagy–lysosomal dysfunction. According to a new study by Sergin et al. published in Nat. Comms., the natural disaccharide trehalose can be used to treat atherosclerosis, given its capacity to induce macrophage autophagy– lysosomal biogenesis. In the first part of their study, the investigators assessed the link between dysfunctional autophagy and atherosclerotic plaque progression in both Apoe-null mice and human plaque samples. Given that the TFEB transcription factor has been shown to promote the prodegradative response in macrophages, the investigators created macrophage-specific TFEB-transgenic mice to assess the effect of TFEB overexpression on atherosclerosis. Overexpression of TFEB induced auto phagosome formation and autophagy– lysosomal biogenesis in macrophages, reversed autophagy dysfunction, and reduced macro phage apoptosis, pro-inflammatory cytokine expression, and plaque complexity. In the second part of the study, the investigators assessed the capacity of the natural disaccharide trehalose to stimulate macrophage autophagy, as it has been previously shown to have similar autophagy-inducing and protein aggregate-reducing effects as TFEB. Trehalose increased TFEB expression, supporting its role in autophagy–lysosomal biogenesis. Trehalose administration was also shown to induce autophagy and TFEB activation in vivo, as well as reducing macrophage apoptosis and pro-inflammatory cytokine expression. “This is the first report demonstrating the use of the natural sugar trehalose in the treatment of atherosclerosis,” the investigators explain. The precise mechanism by which trehalose induces autophagy remains unclear. Karina Huynh AT H E R O S C L E R O S I S