Inhibition of fatty acid oxidation enhances oxidative protein folding and protects hepatocytes from endoplasmic reticulum stress.
Inhibition of fatty acid oxidation enhances oxidative protein folding and protects hepatocytes from endoplasmic reticulum stress.
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DOI：
10.1091/mbc.e11-12-1011
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发表时间：
2012-03
影响因子：
3.3
通讯作者：
Rutkowski DT
中科院分区：
文献类型：
--
作者：
Tyra HM;Spitz DR;Rutkowski DT
未折叠蛋白反应调节脂质代谢，但这种调节对ER功能的功能益处尚不清楚。这项工作表明，抑制脂肪酸氧化提高细胞氧化电位，促进ER氧化折叠，并保护肝细胞免受ER应激。未折叠蛋白反应（UPR）信号蛋白质错误折叠在内质网（ER）的影响基因表达的变化和恢复ER稳态。虽然许多UPR调控基因编码ER蛋白加工因子，但其他基因，如编码脂质过氧化氢酶的基因，似乎与ER功能无关。目前尚不清楚UPR介导的脂肪酸氧化抑制是否会影响ER功能，或者如果是，通过何种机制。在这里，我们证明，药理学或遗传抑制脂肪酸氧化使肝细胞部分抵抗ER应激诱导的UPR激活在体外和体内。降低应激敏感性似乎是细胞氧化还原电位增加的结果，如通过氧化还原型谷胱甘肽的升高比率和ER中氧化折叠的增强来判断的。因此，抑制脂肪酸（FA）氧化的ER折叠的好处可以通过在ER应激期间操纵谷胱甘肽再循环来表型复制。相反，用N-乙酰半胱氨酸防止细胞过氧化部分地否定了通过阻断FA氧化提供的应激抗性。我们的研究结果表明，ER应激可以通过改变ER腔内的氧化环境来改善，并且它们为应激期间UPR对代谢途径的瞬时调节提供了潜在的逻辑。
The unfolded protein response regulates lipid metabolism, but the functional benefit of this regulation to ER function is not clear. This work shows that inhibition of fatty acid oxidation raises cellular oxidation potential, facilitates ER oxidative folding, and protects hepatocytes from ER stress. The unfolded protein response (UPR) signals protein misfolding in the endoplasmic reticulum (ER) to effect gene expression changes and restore ER homeostasis. Although many UPR-regulated genes encode ER protein processing factors, others, such as those encoding lipid catabolism enzymes, seem unrelated to ER function. It is not known whether UPR-mediated inhibition of fatty acid oxidation influences ER function or, if so, by what mechanism. Here we demonstrate that pharmacological or genetic inhibition of fatty acid oxidation renders liver cells partially resistant to ER stress–induced UPR activation both in vitro and in vivo. Reduced stress sensitivity appeared to be a consequence of increased cellular redox potential as judged by an elevated ratio of oxidized to reduced glutathione and enhanced oxidative folding in the ER. Accordingly, the ER folding benefit of inhibiting fatty acid (FA) oxidation could be phenocopied by manipulating glutathione recycling during ER stress. Conversely, preventing cellular hyperoxidation with N-acetyl cysteine partially negated the stress resistance provided by blocking FA oxidation. Our results suggest that ER stress can be ameliorated through alteration of the oxidizing environment within the ER lumen, and they provide a potential logic for the transient regulation of metabolic pathways by the UPR during stress.