Cobalt chloride decreases fibroblast growth factor-21 expression dependent on oxidative stress but not hypoxia-inducible factor in Caco-2 cells.
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 (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-α (HIFα) 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 HIFα, but dependent on an oxidative stress-mediated mechanism. The regulation of FGF21 by hypoxia may contribute to intestinal lipid metabolism and absorption.
School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
Yanlong
Y
Liu
Chunhong
C
Wang
Yuhua
Y
Wang
Zhenhua
Z
Ma
Jian
J
Xiao
Craig
C
McClain
Xiaokun
X
Li
Wenke
W
Feng
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000096:biosynthesis; D001391:Azo Compounds; D015153:Blotting, Western; D018938:Caco-2 Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003035:Cobalt / Q000494:pharmacology*; D004396:Coloring Agents; D005346:Fibroblast Growth Factors / Q000096:biosynthesis*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects*; D047493:PPAR alpha / Q000502:physiology; D047495:PPAR gamma / Q000502:physiology; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis; D060888:Real-Time Polymerase Chain Reaction; D013481:Superoxides / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
D001391:Azo Compounds; D004396:Coloring Agents; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047493:PPAR alpha; D047495:PPAR gamma; D012333:RNA, Messenger; D014280:Triglycerides; C414620:fibroblast growth factor 21; D013481:Superoxides; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003035:Cobalt; D005346:Fibroblast Growth Factors; C018021:cobaltous chloride; C011049:oil red O