PMID- 22917661
OWN - NLM
STAT- MEDLINE
DCOM- 20121204
LR  - 20211021
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Print)
IS  - 0041-008X (Linking)
VI  - 264
IP  - 2
DP  - 2012 Oct 15
TI  - Cobalt chloride decreases fibroblast growth factor-21 expression dependent on 
      oxidative stress but not hypoxia-inducible factor in Caco-2 cells.
PG  - 212-21
LID - S0041-008X(12)00344-4 [pii]
LID - 10.1016/j.taap.2012.08.003 [doi]
AB  - 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.
CI  - Copyright (c) 2012 Elsevier Inc. All rights reserved.
FAU - Liu, Yanlong
AU  - Liu Y
AD  - School of Pharmacy, Wenzhou Medical College, Wenzhou, China.
FAU - Wang, Chunhong
AU  - Wang C
FAU - Wang, Yuhua
AU  - Wang Y
FAU - Ma, Zhenhua
AU  - Ma Z
FAU - Xiao, Jian
AU  - Xiao J
FAU - McClain, Craig
AU  - McClain C
FAU - Li, Xiaokun
AU  - Li X
FAU - Feng, Wenke
AU  - Feng W
LA  - eng
GR  - U01 AA021901/AA/NIAAA NIH HHS/United States
GR  - R01AA015970/AA/NIAAA NIH HHS/United States
GR  - P01 AA017103/AA/NIAAA NIH HHS/United States
GR  - R01DK071765/DK/NIDDK NIH HHS/United States
GR  - RC2AA019385/AA/NIAAA NIH HHS/United States
GR  - R01 AA018016/AA/NIAAA NIH HHS/United States
GR  - P30AA019360/AA/NIAAA NIH HHS/United States
GR  - P30 AA019360/AA/NIAAA NIH HHS/United States
GR  - R37AA010762/AA/NIAAA NIH HHS/United States
GR  - R01 AA015970/AA/NIAAA NIH HHS/United States
GR  - R01AA018869/AA/NIAAA NIH HHS/United States
GR  - R01 AA010496/AA/NIAAA NIH HHS/United States
GR  - P01AA017103/AA/NIAAA NIH HHS/United States
GR  - R01 AA018869/AA/NIAAA NIH HHS/United States
GR  - R01 DK071765/DK/NIDDK NIH HHS/United States
GR  - RC2 AA019385/AA/NIAAA NIH HHS/United States
GR  - R01AA018016/AA/NIAAA NIH HHS/United States
GR  - R37 AA010762/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120810
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (Azo Compounds)
RN  - 0 (Coloring Agents)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (PPAR alpha)
RN  - 0 (PPAR gamma)
RN  - 0 (RNA, Messenger)
RN  - 0 (Triglycerides)
RN  - 0 (fibroblast growth factor 21)
RN  - 11062-77-4 (Superoxides)
RN  - 138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator)
RN  - 3G0H8C9362 (Cobalt)
RN  - 62031-54-3 (Fibroblast Growth Factors)
RN  - EVS87XF13W (cobaltous chloride)
RN  - G7S71FND9B (oil red O)
SB  - IM
MH  - Aryl Hydrocarbon Receptor Nuclear Translocator/biosynthesis
MH  - Azo Compounds
MH  - Blotting, Western
MH  - Caco-2 Cells
MH  - Cell Nucleus/drug effects/metabolism
MH  - Cobalt/*pharmacology
MH  - Coloring Agents
MH  - Fibroblast Growth Factors/*biosynthesis
MH  - Humans
MH  - Hypoxia-Inducible Factor 1/*physiology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis
MH  - Oxidative Stress/*drug effects
MH  - PPAR alpha/physiology
MH  - PPAR gamma/physiology
MH  - RNA Interference
MH  - RNA, Messenger/biosynthesis
MH  - Real-Time Polymerase Chain Reaction
MH  - Superoxides/metabolism
MH  - Triglycerides/metabolism
PMC - PMC3593348
MID - NIHMS405399
COIS- Conflict of Interest Statement: The authors have no conflict of interest to be 
      claimed.
EDAT- 2012/08/25 06:00
MHDA- 2012/12/10 06:00
PMCR- 2013/10/15
CRDT- 2012/08/25 06:00
PHST- 2012/03/19 00:00 [received]
PHST- 2012/08/02 00:00 [revised]
PHST- 2012/08/03 00:00 [accepted]
PHST- 2012/08/25 06:00 [entrez]
PHST- 2012/08/25 06:00 [pubmed]
PHST- 2012/12/10 06:00 [medline]
PHST- 2013/10/15 00:00 [pmc-release]
AID - S0041-008X(12)00344-4 [pii]
AID - 10.1016/j.taap.2012.08.003 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2012 Oct 15;264(2):212-21. doi: 
      10.1016/j.taap.2012.08.003. Epub 2012 Aug 10.