FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway.
FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway.
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DOI：
10.1096/fj.201700709rr
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发表时间：
2018-05
期刊：
影响因子：
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通讯作者：
Chung HT
中科院分区：
文献类型：
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作者：
Joe Y;Kim S;Kim HJ;Park J;Chen Y;Park HJ;Jekal SJ;Ryter SW;Kim UH;Chung HT
包括 2 型糖尿病、肥胖症和心血管疾病在内的代谢疾病的患病率迅速增加，但代谢综合征这一主要危险因素的分子机制仍不完全清楚。气态小分子一氧化碳 (CO) 在多种细胞和组织损伤模型中具有众所周知的抗炎、抗增殖和抗凋亡作用，但其对代谢疾病复杂途径的潜在影响仍不清楚。我们在此证明 CO 可以缓解体内和体外的代谢功能障碍。我们发现，CO 增加了肝细胞和肝脏中成纤维细胞生长因子 21 (FGF21) 的表达和切片。 CO 刺激 PERK 激活并通过 eIF2α-ATF4 信号通路增强 FGF21 的水平。 CO 诱导 FGF21 可减轻网内应激或饮食诱导的肥胖依赖性肝脂肪变性。此外，吸入二氧化碳可以降低血糖水平，增强胰岛素敏感性，并通过刺激白色脂肪细胞产生米色脂肪细胞来促进能量消耗。总之，我们认为 CO 是 FGF21 表达的有效诱导剂，并且 CO 关键依赖 FGF21 来调节代谢稳态。-Joe, Y., Kim, S., Kim, H. J., Park, J., Chen, Y., Park, H.-J., Jekal, S.-J., Ryter, S. W., Kim, U. H., Chung, H. T. 由碳诱导的 FGF21一氧化物通过 PERK/ATF4 途径介导代谢稳态。
The prevalence of metabolic diseases, including type 2 diabetes, obesity, and cardiovascular disease, has rapidly increased, yet the molecular mechanisms underlying the metabolic syndrome, a primary risk factor, remain incompletely understood. The small, gaseous molecule carbon monoxide (CO) has well-known anti-inflammatory, antiproliferative, and antiapoptotic effects in a variety of cellular- and tissue-injury models, whereas its potential effects on the complex pathways of metabolic disease remain unknown. We demonstrate here that CO can alleviate metabolic dysfunction in vivo and in vitro. We show that CO increased the expression and section of the fibroblast growth factor 21 (FGF21) in hepatocytes and liver. CO-stimulated PERK activation and enhanced the levels of FGF21 via the eIF2α–ATF4 signaling pathway. The induction of FGF21 by CO attenuated endoreticulum stress- or diet-induced, obesity-dependent hepatic steatosis. Moreover, CO inhalation lowered blood glucose levels, enhanced insulin sensitivity, and promoted energy expenditure by stimulating the emergence of beige adipose cells from white adipose cells. In conclusion, we suggest that CO acts as a potent inducer of FGF21 expression and that CO critically depends on FGF21 to regulate metabolic homeostasis.—Joe, Y., Kim, S., Kim, H. J., Park, J., Chen, Y., Park, H.-J., Jekal, S.-J., Ryter, S. W., Kim, U. H., Chung, H. T. FGF21 induced by carbon monoxide mediates metabolic homeostasis via the PERK/ATF4 pathway.