PMID- 24632196
OWN - NLM
STAT- MEDLINE
DCOM- 20150106
LR  - 20201025
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 71
DP  - 2014 Jun
TI  - Mechanism for HIF-1 activation by cholesterol under normoxia: a redox signaling 
      pathway for liver damage.
PG  - 61-69
LID - S0891-5849(14)00122-1 [pii]
LID - 10.1016/j.freeradbiomed.2014.03.007 [doi]
AB  - Cholesterol and chronic activation of hypoxia-inducible factor-1 (HIF-1) have 
      been separately implicated in the pathogenesis and progression of liver diseases. 
      In AML12 hepatocytes increased HIF-1alpha protein accumulation was evident after 2 h 
      of incubation with cholesterol, whereas enhanced HIF-1 transcriptional activity 
      was observed after 6 h. Investigations into the molecular mechanism have shown 
      that cholesterol inhibited HIF-1alpha degradation. Mitochondrial dysfunction and 
      enhanced mitochondrial reactive oxygen species (ROS) generation were observed in 
      2-h cholesterol-treated cells along with augmented nitric oxide (NO) levels. 
      Further analysis indicated that HIF-1alpha stabilization at later time (6h), but not 
      after 2h, of incubation with cholesterol was dependent on NO production. To 
      elucidate the role of mitochondrial dysfunction in HIF-1alpha stabilization, 
      mitochondrial DNA-depleted hepatocytes were prepared. In these cells the ability 
      of cholesterol to activate the HIF-1 pathway was abolished. Similarly, catalase 
      overexpression also attenuated cholesterol-induced HIF-1alpha accumulation. These 
      results demonstrate that cholesterol promotes HIF-1 activation in a ROS- and 
      NO-dependent manner. Chronic liver activation of HIF-1 by cholesterol may mediate 
      its deleterious effects in the liver.
CI  - Copyright (c) 2014 Elsevier Inc. All rights reserved.
FAU - Anavi, Sarit
AU  - Anavi S
AD  - The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of 
      Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, 
      Rehovot 76100, Israel.
FAU - Hahn-Obercyger, Michal
AU  - Hahn-Obercyger M
AD  - The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of 
      Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, 
      Rehovot 76100, Israel.
FAU - Madar, Zecharia
AU  - Madar Z
AD  - The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of 
      Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, 
      Rehovot 76100, Israel.
FAU - Tirosh, Oren
AU  - Tirosh O
AD  - The Robert H. Smith Faculty of Agriculture, Food, and Environment, Institute of 
      Biochemistry, Food Science, and Nutrition, The Hebrew University of Jerusalem, 
      Rehovot 76100, Israel. Electronic address: oren.tirosh@mail.huji.ac.il.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140313
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Reactive Oxygen Species)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 1.11.1.6 (Catalase)
SB  - IM
MH  - Animals
MH  - Catalase/genetics/metabolism
MH  - Cell Line
MH  - Cholesterol/*pharmacology
MH  - DNA, Mitochondrial/*metabolism
MH  - Gene Expression Regulation
MH  - Hepatocytes/cytology/*drug effects/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*agonists/genetics/metabolism
MH  - Mice
MH  - Mitochondria/*drug effects/metabolism
MH  - Nitric Oxide/metabolism
MH  - Oxidation-Reduction
MH  - Proteolysis
MH  - Reactive Oxygen Species/metabolism
MH  - Signal Transduction/*genetics
MH  - Transcription, Genetic
OTO - NOTNLM
OT  - Free radicals
OT  - Inflammation
OT  - Lipids
OT  - Nonalcoholic steatohepatitis
OT  - Oxidative stress
OT  - Redox signaling
EDAT- 2014/03/19 06:00
MHDA- 2015/01/07 06:00
CRDT- 2014/03/18 06:00
PHST- 2013/08/18 00:00 [received]
PHST- 2014/02/03 00:00 [revised]
PHST- 2014/03/04 00:00 [accepted]
PHST- 2014/03/18 06:00 [entrez]
PHST- 2014/03/19 06:00 [pubmed]
PHST- 2015/01/07 06:00 [medline]
AID - S0891-5849(14)00122-1 [pii]
AID - 10.1016/j.freeradbiomed.2014.03.007 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2014 Jun;71:61-69. doi: 10.1016/j.freeradbiomed.2014.03.007. 
      Epub 2014 Mar 13.