Cobalt chloride decreases fibroblast growth factor-21 expression dependent on oxidative stress but not hypoxia-inducible factor in Caco-2 cells

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• 作者：Yanlong Liu ; Chunhong Wang ; Yuhua Wang ; Zhenhua Ma ; Jian Xiao ; Craig McClain ; Xiaokun Li ; Wenke Feng
• 关键词：Fibroblast growth factor-21 ; Hypoxia ; Cobalt chloride ; Hypoxia-inducible factor ; Caco-2
• 刊名：Toxicology and Applied Pharmacology
• 出版年：2012
• 出版时间：15 October, 2012
• 年：2012
• 卷：264
• 期：2
• 页码：212-221
• 全文大小：1060 K

文摘

Fibroblast growth factor-21 (FGF21) is a potential metabolic regulator with multiple beneficial effects on metabolic diseases. FGF21 is mainly expressed in the liver, but is also found in other tissues including the intestine, which expresses ¦Â-klotho abundantly. The intestine is a unique organ that operates in a physiologically hypoxic environment, and is responsible for the fat absorption processes including triglyceride breakdown, re-synthesis and absorption into the portal circulation. In the present study, we investigated the effects of hypoxia and the chemical hypoxia inducer, cobalt chloride (CoCl₂), on FGF21 expression in Caco-2 cells and the consequence of fat accumulation. Physical hypoxia (1 % oxygen) and CoCl₂ treatment decreased both FGF21 mRNA and secreted protein levels. Gene silence and inhibition of hypoxia-inducible factor-¦Á (HIF¦Á) did not affect the reduction of FGF21 mRNA and protein levels by hypoxia. However, CoCl₂ administration caused a significant increase in oxidative stress. The addition of n-acetylcysteine (NAC) suppressed CoCl₂-induced reactive oxygen species (ROS) formation and completely negated CoCl₂-induced FGF21 loss. mRNA stability analysis demonstrated that the CoCl₂ administration caused a remarkable reduction in FGF21 mRNA stability. Furthermore, CoCl₂ increased intracellular triglyceride (TG) accumulation, along with a reduction in mRNA levels of lipid lipase, hormone sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), and an increase of sterol regulatory element-binding protein-1c (SREBP1c) and stearoyl-coenzyme A (SCD1). Addition of both NAC and recombinant FGF21 significantly attenuated the CoCl₂-induced TG accumulation. In conclusion, the decrease of FGF21 in Caco-2 cells by chemical hypoxia is independent of HIF¦Á, but dependent on an oxidative stress-mediated mechanism. The regulation of FGF21 by hypoxia may contribute to intestinal lipid metabolism and absorption.