Nuclear Perilipin 5 integrates lipid droplet lipolysis with PGC-1α/SIRT1-dependent transcriptional regulation of mitochondrial function.
Nuclear Perilipin 5 integrates lipid droplet lipolysis with PGC-1α/SIRT1-dependent transcriptional regulation of mitochondrial function.
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DOI：
10.1038/ncomms12723
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发表时间：
2016-08-24
影响因子：
16.6
通讯作者：
Bickel PE
中科院分区：
文献类型：
--
作者：
Gallardo-Montejano VI;Saxena G;Kusminski CM;Yang C;McAfee JL;Hahner L;Hoch K;Dubinsky W;Narkar VA;Bickel PE
细胞脂质代谢功能障碍导致常见的慢性人类疾病，包括2型糖尿病、肥胖症、脂肪肝和糖尿病性心肌病。细胞如何平衡脂质储存和线粒体氧化能力知之甚少。在这里，我们确定脂滴蛋白Perilipin 5作为PGC-1α的儿茶酚胺触发的相互作用伴侣。我们报道了在儿茶酚胺刺激的脂解过程中，Perilipin 5被蛋白激酶A磷酸化，并在细胞核中与PGC-1α和SIRT 1形成转录复合物。Perilipin 5通过解除SIRT 1脱乙酰酶活性抑制促进PGC-1α共激活因子功能。我们通过细胞功能的获得和丧失研究表明，核周脂蛋白5促进介导线粒体生物合成和氧化功能的基因的转录。我们认为Perilipin 5是一个重要的分子连接，它将PKA通路的协调儿茶酚胺激活和脂滴脂解与转录调控偶联，以促进有效的脂肪酸催化剂和防止线粒体功能障碍。 周脂蛋白5被认为是脂肪酶活性的调节剂和连接脂滴与线粒体的支架。在这里，作者表明PKA刺激Peripilin 5与核PGC-1a和SIRT 1的相互作用，以促进调节线粒体生物发生和呼吸的基因的转录。
Dysfunctional cellular lipid metabolism contributes to common chronic human diseases, including type 2 diabetes, obesity, fatty liver disease and diabetic cardiomyopathy. How cells balance lipid storage and mitochondrial oxidative capacity is poorly understood. Here we identify the lipid droplet protein Perilipin 5 as a catecholamine-triggered interaction partner of PGC-1α. We report that during catecholamine-stimulated lipolysis, Perilipin 5 is phosphorylated by protein kinase A and forms transcriptional complexes with PGC-1α and SIRT1 in the nucleus. Perilipin 5 promotes PGC-1α co-activator function by disinhibiting SIRT1 deacetylase activity. We show by gain-and-loss of function studies in cells that nuclear Perilipin 5 promotes transcription of genes that mediate mitochondrial biogenesis and oxidative function. We propose that Perilipin 5 is an important molecular link that couples the coordinated catecholamine activation of the PKA pathway and of lipid droplet lipolysis with transcriptional regulation to promote efficient fatty acid catabolism and prevent mitochondrial dysfunction. Perilipin 5 has been implicated as a modulator of lipase activity and a scaffold linking lipid droplets to mitochondria. Here the authors show that PKA stimulates Peripilin 5 interaction with nuclear PGC-1a and SIRT1 to promote transcription of genes regulating mitochondrial biogenesis and respiration.