Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis.
Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis.
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DOI：
10.1038/s42255-021-00489-2
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发表时间：
2021-12
影响因子：
20.8
通讯作者：
Wolfrum C
中科院分区：
文献类型：
--
作者：
Ding L;Sun W;Balaz M;He A;Klug M;Wieland S;Caiazzo R;Raverdy V;Pattou F;Lefebvre P;Lodhi IJ;Staels B;Heim M;Wolfrum C
为了从细胞内储存中释放脂肪酸（FA），脂解由脂肪酶脂肪甘油三酯脂肪酶（ATGL）、脂肪酶敏感性脂肪酶和单酰基甘油脂肪酶的活性调节。由于不受控制的脂解导致的过量FA释放导致脂毒性，这反过来又会促进代谢紊乱的进展。然而，细胞是否可以直接感知脂肪酸，以维持细胞脂质稳态是未知的。在这里，我们报告了一个传感机制的基础上过氧化物酶体降解的脂肪酸，再加上活性氧（ROS）的生产，这反过来又调节脂肪酸的释放，通过调节脂解细胞脂肪酸。ROS水平的变化由PEX 2感知，PEX 2通过翻译后泛素化调节ATGL水平。我们证明了这种途径对非酒精性脂肪肝疾病进展的重要性，使用遗传和药理学方法来改变体内ROS水平，这可用于增加肝脏ATGL水平和改善肝脏脂肪变性。这种过氧化物酶体β-氧化介导的反馈机制在多个器官中是保守的，其发现将过氧化物酶体和脂滴的功能偶联，并且可能作为操纵脂解以治疗代谢紊乱的新途径。Ding等人报道了一种允许细胞感知细胞脂肪酸水平并根据需要调节脂解的机制，其涉及脂肪酸的过氧化物酶体降解、活性氧的产生和脂肪甘油三酯脂肪酶的翻译后调节。
To liberate fatty acids (FAs) from intracellular stores, lipolysis is regulated by the activity of the lipases adipose triglyceride lipase (ATGL), hormone-sensitive lipase and monoacylglycerol lipase. Excessive FA release as a result of uncontrolled lipolysis results in lipotoxicity, which can in turn promote the progression of metabolic disorders. However, whether cells can directly sense FAs to maintain cellular lipid homeostasis is unknown. Here we report a sensing mechanism for cellular FAs based on peroxisomal degradation of FAs and coupled with reactive oxygen species (ROS) production, which in turn regulates FA release by modulating lipolysis. Changes in ROS levels are sensed by PEX2, which modulates ATGL levels through post-translational ubiquitination. We demonstrate the importance of this pathway for non-alcoholic fatty liver disease progression using genetic and pharmacological approaches to alter ROS levels in vivo, which can be utilized to increase hepatic ATGL levels and ameliorate hepatic steatosis. The discovery of this peroxisomal β-oxidation-mediated feedback mechanism, which is conserved in multiple organs, couples the functions of peroxisomes and lipid droplets and might serve as a new way to manipulate lipolysis to treat metabolic disorders. Ding et al. report a mechanism that allows cells to sense cellular fatty acid levels and adjust lipolysis as needed, which involves peroxisomal degradation of fatty acids, production of reactive oxygen species and post-translational regulation of adipose triglyceride lipase.
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DOI：
10.1083/jcb.201511034
发表时间：
2016-09-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Sargent G;van Zutphen T;Shatseva T;Zhang L;Di Giovanni V;Bandsma R;Kim PK
通讯作者：
Kim PK
影响因子：
7.7
作者：
Ghosh, Mainak;Niyogi, Sougata;Chakrabartil, Partha
通讯作者：
Chakrabartil, Partha
影响因子：
6.5
作者：
Iglesias, Jose;Lamontagne, Julien;Prentki, Marc
通讯作者：
Prentki, Marc
影响因子：
7.8
作者：
Chang, Chi-Lun;Weigel, Aubrey, V;Lippincott-Schwartz, Jennifer
通讯作者：
Lippincott-Schwartz, Jennifer
影响因子：
6.6
作者：
Maller, Claire;Schroeder, Ewald;Eaton, Philip
通讯作者：
Eaton, Philip