PMID- 30036883
OWN - NLM
STAT- MEDLINE
DCOM- 20180904
LR  - 20200225
IS  - 1421-9778 (Electronic)
IS  - 1015-8987 (Print)
IS  - 1015-8987 (Linking)
VI  - 48
IP  - 3
DP  - 2018
TI  - Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis.
PG  - 1003-1011
LID - 10.1159/000491968 [doi]
AB  - BACKGROUND/AIMS: Liver disease is a leading cause of high mortality and morbidity 
      worldwide. The aim of the present study is to investigate the regulatory role of 
      prolyl hydroxylase-2 (PHD2)-hypoxia-inducible factor-2a (HIF-2alpha) axis on 
      nonalcoholic fatty liver disease (NAFLD) and to explore the potential mechanisms 
      by which endothelial (EC)-specific PHD2 deficiency regulates hepatic steatosis 
      and fibrosis. METHODS: In the endothelial-specific PHD2 knockout (PHD2ECKO) mouse 
      fed with normal diet or high fat diet (HFD), liver lipid accumulation and 
      fibrosis were measured by Oil Red O and Masson trichrome staining. The fat and 
      body weight (FW/BW) ratio and glucose tolerance were measured. The expression of 
      HIF-2alpha, atrial natriuretic peptide (ANP), angiopoietin-2 (Ang-2), and 
      transforming growth factor-b (TGF-beta) were analyzed by western blot analysis. 
      RESULTS: The steatosis and fibrosis were significantly increased in the PHD2ECKO 
      mice. FW/BW ratio was significantly increased in the PHD2ECKO mice. Moreover, 
      knockout of endothelial PHD2 resulted in an impairment of glucose tolerance in 
      mice. Western blot analysis showed that the expression of HIF-2alpha in liver tissues 
      was not significantly increased. Interestingly, the expression of ANP was 
      decreased, and Ang-2 and TGF-beta levels were significantly increased in the liver 
      of PHD2ECKO mice. The FW/BW ratio was also significantly increased in the 
      PHD2ECKO mice fed with HFD for 16 weeks. Feeding HFD resulted in a significant 
      increase in hepatic steatosis in the control PHD2f/f mice, but did not further 
      enhance hepatic steatosis in the PHD2ECKO mice. CONCLUSIONS: We concluded that 
      the endothelial PHD2 plays a critical role in hepatic steatosis and fibrosis, 
      which may be involved in the regulation of ANP and Ang-2/TGF-beta signaling pathway, 
      but not the HIF-2alpha expression.
CI  - (c) 2018 The Author(s). Published by S. Karger AG, Basel.
FAU - Zhou, Li-Ying
AU  - Zhou LY
AD  - Department of Pharmacology and Toxicology, University of Mississippi Medical 
      Center, School of Medicine, Jackson, Mississippi, USA.
AD  - Department of Reproduction, Beijing Obstetrics and Gynecology Hospital, Capital 
      Medical University, Beijing, China.
FAU - Zeng, Heng
AU  - Zeng H
AD  - Department of Pharmacology and Toxicology, University of Mississippi Medical 
      Center, School of Medicine, Jackson, Mississippi, USA.
FAU - Wang, Shuo
AU  - Wang S
AD  - Department of Pharmacology and Toxicology, University of Mississippi Medical 
      Center, School of Medicine, Jackson, Mississippi, USA.
AD  - Key laboratory of cerebral cardiopulmonary Resuscitation, Beijing Chao-Yang 
      Hospital, Capital Medical University, Beijing, China.
FAU - Chen, Jian-Xiong
AU  - Chen JX
AD  - Department of Pharmacology and Toxicology, University of Mississippi Medical 
      Center, School of Medicine, Jackson, Mississippi, USA.
LA  - eng
GR  - R01 HL102042/HL/NHLBI NIH HHS/United States
PT  - Journal Article
DEP - 20180723
PL  - Germany
TA  - Cell Physiol Biochem
JT  - Cellular physiology and biochemistry : international journal of experimental 
      cellular physiology, biochemistry, and pharmacology
JID - 9113221
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (Transforming Growth Factor beta)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - 85637-73-6 (Atrial Natriuretic Factor)
RN  - EC 1.14.11.29 (Egln1 protein, mouse)
RN  - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases)
RN  - EC 2.7.1.105 (PFKFB3 protein, mouse)
RN  - EC 2.7.1.105 (Phosphofructokinase-2)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 3.1.27.5 (Ang2 protein, mouse)
RN  - EC 3.1.27.5 (Ribonuclease, Pancreatic)
SB  - IM
MH  - Animals
MH  - Atrial Natriuretic Factor/metabolism
MH  - Basic Helix-Loop-Helix Transcription Factors/metabolism
MH  - Diet, High-Fat
MH  - Endothelium/*metabolism
MH  - Glucose Tolerance Test
MH  - Hypoxia-Inducible Factor-Proline Dioxygenases/deficiency/genetics/*metabolism
MH  - Liver/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Non-alcoholic Fatty Liver Disease/metabolism/*pathology/veterinary
MH  - Phosphofructokinase-2/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Ribonuclease, Pancreatic/metabolism
MH  - Signal Transduction
MH  - Transforming Growth Factor beta/metabolism
PMC - PMC6350253
MID - NIHMS1007916
OTO - NOTNLM
OT  - Atrial natriuretic peptide (ANP)
OT  - Endothelium
OT  - HIF-2alpha
OT  - Hepatic Steatosis
OT  - Phd2
COIS- Disclosure Statement The authors have no conflicts of interest associated with 
      this manuscript.
EDAT- 2018/07/24 06:00
MHDA- 2018/09/05 06:00
PMCR- 2019/01/29
CRDT- 2018/07/24 06:00
PHST- 2018/01/24 00:00 [received]
PHST- 2018/05/25 00:00 [accepted]
PHST- 2018/07/24 06:00 [pubmed]
PHST- 2018/09/05 06:00 [medline]
PHST- 2018/07/24 06:00 [entrez]
PHST- 2019/01/29 00:00 [pmc-release]
AID - 000491968 [pii]
AID - 10.1159/000491968 [doi]
PST - ppublish
SO  - Cell Physiol Biochem. 2018;48(3):1003-1011. doi: 10.1159/000491968. Epub 2018 Jul 
      23.