FoxO1 controls lysosomal acid lipase in adipocytes: implication of lipophagy during nutrient restriction and metformin treatment.
FoxO1 controls lysosomal acid lipase in adipocytes: implication of lipophagy during nutrient restriction and metformin treatment.
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DOI：
10.1038/cddis.2013.404
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发表时间：
2013-10-17
影响因子：
9
通讯作者：
Ciriolo, M. R.
中科院分区：
文献类型：
--
作者：
Barbato, D. Lettieri;Tatulli, G.;Aquilano, K.;Ciriolo, M. R.
寻找新的调控脂肪细胞脂解的分子途径和策略是当前研究的一个有吸引力的目标。事实上，越来越清楚的是，几种人类年龄相关的病理是由脂肪组织扩张和脂质代谢改变引起的。在目前的工作中，我们表明，转录因子叉头同源异型盒蛋白O1（FoxO1）的上调营养限制（NR）在脂肪细胞中，并通过诱导溶酶体酸性脂肪酶（利帕）发挥脂质catalysts的转录控制。观察到脂滴（LD）与溶酶体的自噬和共定位增加，这意味着在Lipa介导的LD降解中存在脂肪吞噬作用。有趣的是，我们发现二甲双胍（Metf），一种常用于治疗2型糖尿病的双胍类药物，发挥的作用与NR相当。实际上，它能够引起FoxO 1依赖性利帕诱导以及通过脂肪吞噬降解LD。此外，我们证明，在NR或Metf治疗期间，由利帕释放的游离脂肪酸被导向AMP激活的蛋白激酶介导的线粒体氧化，从而维持脂肪细胞的能量稳态。总之，我们的数据表明，溶酶体介导的脂质catalysts被激活的NR在脂肪细胞中，并给予进一步的支持使用Metf作为NR模拟物，以打击与脂质代谢改变相关的年龄相关性疾病。
Finding new molecular pathways and strategies modulating lipolysis in adipocytes is an attractive goal of the current research. Indeed, it is becoming clear that several human age-related pathologies are caused by adipose tissue expansion and altered lipid metabolism. In the present work, we show that transcription factor forkhead homeobox type protein O1 (FoxO1) is upregulated by nutrient restriction (NR) in adipocytes and exerts the transcriptional control of lipid catabolism via the induction of lysosomal acid lipase (Lipa). An increased autophagy and colocalization of lipid droplets (LDs) with lysosomes was observed implying lipophagy in Lipa-mediated LDs degradation. Interestingly, we found that metformin (Metf), a biguanide drug commonly used to treat type-2 diabetes, exerts effects comparable to that of NR. Actually, it was able to elicit FoxO1-dependent Lipa induction as well as LDs degradation through lipophagy. Moreover, we demonstrate that, during NR or Metf treatment, free fatty acids released by Lipa are directed toward AMP-activated protein kinase-mediated mitochondrial oxidation, thus maintaining energetic homeostasis in adipocytes. In conclusion, our data show that lysosomal-mediated lipid catabolism is activated by NR in adipocytes and give further support to the use of Metf as a NR mimetic to combat age-related diseases associated with altered lipid metabolism.
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