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

• Published in: Toxicology and applied pharmacology 2012-10, Vol.264 (2), p.212-221
• Main Authors: Liu, Yanlong, Wang, Chunhong, Wang, Yuhua, Ma, Zhenhua, Xiao, Jian, McClain, Craig, Li, Xiaokun, Feng, Wenke
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ABSORPTION; Acetylcysteine; ANIMAL TISSUES; ANOXIA; ANTIOXIDANTS; Aryl Hydrocarbon Receptor Nuclear Translocator - biosynthesis; Azo Compounds; Biological and medical sciences; BIOLOGICAL STRESS; Blotting, Western; Caco-2; Caco-2 Cells; Cell Nucleus - drug effects; Cell Nucleus - metabolism; CELL PROLIFERATION; Cobalt - pharmacology; Cobalt chloride; COBALT CHLORIDES; COENZYMES; Coloring Agents; CYSTEINE; FATS; Fibroblast growth factor-21; Fibroblast Growth Factors - biosynthesis; FIBROBLASTS; Gene silencing; GROWTH FACTORS; HORMONES; Humans; Hypoxia; Hypoxia-inducible factor; Hypoxia-Inducible Factor 1 - physiology; Hypoxia-Inducible Factor 1, alpha Subunit - biosynthesis; Hypoxia-inducible factors; INHIBITION; Intestine; INTESTINES; LIPASES; Lipid metabolism; LIVER; Medical sciences; MESSENGER-RNA; METABOLIC DISEASES; Metabolic disorders; mRNA stability; OXIDATION; Oxidative stress; Oxidative Stress - drug effects; PPAR alpha - physiology; PPAR gamma - physiology; Reactive oxygen species; Real-Time Polymerase Chain Reaction; RNA Interference; RNA, Messenger - biosynthesis; STEROLS; Superoxides - metabolism; Toxicology; Triacylglycerol lipase; TRIGLYCERIDES; Triglycerides - metabolism
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.08.003

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 β-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-α (HIFα) 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 HIFα, but dependent on an oxidative stress-mediated mechanism. The regulation of FGF21 by hypoxia may contribute to intestinal lipid metabolism and absorption. Physical and chemical hypoxia decrease FGF-21 expression, which is inhibited by antioxidant, N-acetyl cysteine (NAC), in Caco-2 cells. [Display omitted] ► Hypoxia down-regulates FGF21 expression in Caco-2 cells. ► FGF21 down-regulation is HIF-α independent. ► FGF21 down-regulation is modulated by oxidative stress-mediated mRNA stability. ► FGF21 is involved in hypoxia‐induced triglyceride accumulation in Caco-2 cells.