Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Department of Radiology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA.
Nat Commun. 2023 Mar 13;14(1):1362. doi: 10.1038/s41467-023-37016-8.
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.
脂肪细胞通过从头合成（DNL）途径从碳水化合物中大量合成脂肪酸（FA），但令人惊讶的是，DNL 对其储存在脂滴中的大量甘油三酯的贡献很小。这一难题提出了一个假设，即脂肪细胞的 DNL 反而能够为自噬等过程中的膜扩张提供支持，而自噬过程需要大量的磷脂供应。我们在这里报告，体外和体内脂肪细胞 Fasn 缺乏显着损害自噬，这表现在自噬体积累和自噬底物 p62 的严重降解受损。我们的数据表明，损伤发生在自噬体-溶酶体融合的水平上，事实上，Fasn 的缺失减少了自噬体和溶酶体成熟和融合所必需的某些膜磷酸肌醇。在培养的脂肪细胞中，外源性 FA 并不能完全缓解 Fasn 对 FA 的依赖性，有趣的是，成像研究表明 Fasn 与新形成的自噬体共定位。总之，我们的研究确定 DNL 是为脂肪细胞中的自噬体和溶酶体成熟和融合提供 FA 的关键来源。
