Iron increases lipid deposition via oxidative stress-mediated mitochondrial dysfunction and the HIF1α-PPARγ pathway
Iron increases lipid deposition via oxidative stress-mediated mitochondrial dysfunction and the HIF1α-PPARγ pathway
复制标题
铁通过氧化应激介导的线粒体功能障碍和HIF 1 α-PPARγ途径增加脂质沉积
DOI：
10.1007/s00018-022-04423-x
复制
发表时间：
2022-07-01
影响因子：
8
通讯作者：
Luo, Zhi
中科院分区：
文献类型：
--
作者：
Song, Chang-Chun;Pantopoulos, Kostas;Luo, Zhi
铁是一种必需的微量元素，参与脊椎动物的多种生物学活动。过多的铁蓄积被认为是脂肪沉积的重要介质。然而，潜在的机制仍不清楚。在目前的研究中，我们发现高铁饮食显著增加了肠道铁含量，并上调了两种铁转运蛋白(zip14和fpn1)的mRNA表达。肠道铁负荷增加脂肪生成，减少脂肪分解，促进氧化应激和线粒体功能障碍。铁诱导的脂质堆积是由低氧诱导因子-1α(HIF1α)介导的，HIF1α是在抑制脯氨酸羟基酶2(PHD2)后诱导的线粒体氧化应激反应。在机制上，铁通过提高HIF1α与PPARγ和Fas启动子的DNA结合能力来促进脂质沉积。我们的结果提供了实验证据，证明氧化应激、线粒体功能障碍和HIF1α-PPAR伽马通路是铁诱导脂肪沉积的关键介质。
Iron is an essential micro-element, involved in multiple biological activities in vertebrates. Excess iron accumulation has been identified as an important mediator of lipid deposition. However, the underlying mechanisms remain unknown. In the present study, we found that a high-iron diet significantly increased intestinal iron content and upregulated the mRNA expression of two iron transporters (zip14 and fpn1). Intestinal iron overload increased lipogenesis, reduced lipolysis and promoted oxidative stress and mitochondrial dysfunction. Iron-induced lipid accumulation was mediated by hypoxia-inducible factor-1 alpha (HIF1 alpha), which was induced in response to mitochondrial oxidative stress following inhibition of prolyl hydroxylase 2 (PHD2). Mechanistically, iron promoted lipid deposition by enhancing the DNA binding capacity of HIF1 alpha to the ppar gamma and fas promoters. Our results provide experimental evidence that oxidative stress, mitochondrial dysfunction and the HIF1 alpha-PPAR gamma pathway are critical mediators of iron-induced lipid deposition.