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De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics

Rowland, Leslie A
Guilherme, Adilson
Henriques, Felipe
DiMarzio, Chloe
Munroe, Sean
Wetoska, Nicole
Kelly, Mark
Reddig, Keith
Hendricks, Gregory
Pan, Meixia
... show 4 more
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Abstract

Adipocytes robustly synthesize fatty acids (FA) from carbohydrate through the de novo lipogenesis (DNL) pathway, yet surprisingly DNL contributes little to their abundant triglyceride stored in lipid droplets. This conundrum raises the hypothesis that adipocyte DNL instead enables membrane expansions to occur in processes like autophagy, which requires an abundant supply of phospholipids. We report here that adipocyte Fasn deficiency in vitro and in vivo markedly impairs autophagy, evident by autophagosome accumulation and severely compromised degradation of the autophagic substrate p62. Our data indicate the impairment occurs at the level of autophagosome-lysosome fusion, and indeed, loss of Fasn decreases certain membrane phosphoinositides necessary for autophagosome and lysosome maturation and fusion. Autophagy dependence on FA produced by Fasn is not fully alleviated by exogenous FA in cultured adipocytes, and interestingly, imaging studies reveal that Fasn colocalizes with nascent autophagosomes. Together, our studies identify DNL as a critical source of FAs to fuel autophagosome and lysosome maturation and fusion in adipocytes.

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Rowland LA, Guilherme A, Henriques F, DiMarzio C, Munroe S, Wetoska N, Kelly M, Reddig K, Hendricks G, Pan M, Han X, Ilkayeva OR, Newgard CB, Czech MP. De novo lipogenesis fuels adipocyte autophagosome and lysosome membrane dynamics. Nat Commun. 2023 Mar 13;14(1):1362. doi: 10.1038/s41467-023-37016-8. PMID: 36914626; PMCID: PMC10011520.

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DOI
10.1038/s41467-023-37016-8
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36914626
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This article is based on a previously available preprint in bioRxiv, https://doi.org/10.1101/2022.05.25.493413.

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© The Author(s) 2023. Open Access: This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/ licenses/by/4.0/.; Attribution 4.0 International