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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Liu Y, Wang C, Wang Y, Ma Z, Xiao J, McClain C, Li X, Feng W
Cobalt chloride decreases fibroblast growth factor-21 expression dependent on oxidative stress but not hypoxia-inducible factor in Caco-2 cells.
Toxicol Appl Pharmacol. 2012 Oct 15;264(2):212-21. doi: 10.1016/j.taap.2012.08.003. Epub 2012 Aug 10.
- PubMed ID
- 22917661 [ View in PubMed]
- Abstract
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 beta-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 (CoCl(2)), on FGF21 expression in Caco-2 cells and the consequence of fat accumulation. Physical hypoxia (1% oxygen) and CoCl(2) treatment decreased both FGF21 mRNA and secreted protein levels. Gene silence and inhibition of hypoxia-inducible factor-alpha (HIFalpha) did not affect the reduction of FGF21 mRNA and protein levels by hypoxia. However, CoCl(2) administration caused a significant increase in oxidative stress. The addition of n-acetylcysteine (NAC) suppressed CoCl(2)-induced reactive oxygen species (ROS) formation and completely negated CoCl(2)-induced FGF21 loss. mRNA stability analysis demonstrated that the CoCl(2) administration caused a remarkable reduction in FGF21 mRNA stability. Furthermore, CoCl(2) 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 CoCl(2)-induced TG accumulation. In conclusion, the decrease of FGF21 in Caco-2 cells by chemical hypoxia is independent of HIFalpha, but dependent on an oxidative stress-mediated mechanism. The regulation of FGF21 by hypoxia may contribute to intestinal lipid metabolism and absorption.