PMID- 24260182
OWN - NLM
STAT- MEDLINE
DCOM- 20140707
LR  - 20240313
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 11
DP  - 2013
TI  - The heme oxygenase system rescues hepatic deterioration in the condition of 
      obesity co-morbid with type-2 diabetes.
PG  - e79270
LID - 10.1371/journal.pone.0079270 [doi]
LID - e79270
AB  - The prevalence of non-alcoholic fatty-liver disease (NAFLD) is increasing 
      globally. NAFLD is a spectrum of related liver diseases that progressive from 
      simple steatosis to serious complications like cirrhosis. The major 
      pathophysiological driving of NAFLD includes elevated hepatic adiposity, 
      increased hepatic triglycerides/cholesterol, excessive hepatic inflammation, and 
      hepatocyte ballooning injury is a common histo-pathological denominator. Although 
      heme-oxygenase (HO) is cytoprotective, its effects on hepatocyte ballooning 
      injury have not been reported. We investigated the effects of upregulating HO 
      with hemin or inhibiting it with stannous-mesoporphyrin (SnMP) on hepatocyte 
      ballooning injury, hepatic adiposity and inflammation in Zucker-diabetic-fatty 
      rats (ZDFs), an obese type-2-diabetic model. Hemin administration to ZDFs abated 
      hepatic/plasma triglycerides and cholesterol, and suppressed several 
      pro-inflammatory cytokines and chemokines including, TNF-alpha, IL-6, IL-1beta, 
      macrophage-inflammatory-protein-1alpha (MIP-1alpha) and 
      macrophage-chemoattractant-protein-1 (MCP-1), with corresponding reduction of the 
      pro-inflammatory M1-phenotype marker, ED1 and hepatic macrophage infiltration. 
      Correspondingly, hemin concomitantly potentiated the protein expression of 
      several markers of the anti-inflammatory macrophage-M2-phenotype including ED2, 
      IL-10 and CD-206, alongside components of the HO-system including HO-1, 
      HO-activity and cGMP, whereas the HO-inhibitor, SnMP abolished the effects. 
      Furthermore, hemin attenuated liver histo-pathological lesions like hepatocyte 
      ballooning injury and fibrosis, and reduced extracellular-matrix/profibrotic 
      proteins implicated in liver injury such as osteopontin, TGF-beta1, fibronectin and 
      collagen-IV. We conclude that hemin restore hepatic morphology by abating hepatic 
      adiposity, suppressing macrophage infiltration, inflammation and fibrosis. The 
      selective enhancement of anti-inflammatory macrophage-M2-phenotype with parallel 
      reduction of pro-inflammatory macrophage-M1-phenotype and related 
      chemokines/cytokines like TNF-alpha, IL-6, IL-1beta, MIP-1alpha and MCP-1 are among the 
      multifaceted mechanisms by which hemin restore hepatic morphology.
FAU - Salley, Tatiana Ntube
AU  - Salley TN
AD  - Department of Physiology, University of Saskatchewan College of Medicine, 
      Saskatoon, Saskatchewan, Canada.
FAU - Mishra, Manish
AU  - Mishra M
FAU - Tiwari, Shuchita
AU  - Tiwari S
FAU - Jadhav, Ashok
AU  - Jadhav A
FAU - Ndisang, Joseph Fomusi
AU  - Ndisang JF
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131115
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cytokines)
RN  - 743LRP9S7N (Hemin)
RN  - EC 1.14.14.18 (Heme Oxygenase (Decyclizing))
RN  - EC 1.14.14.18 (Hmox1 protein, rat)
SB  - IM
MH  - Animals
MH  - Cytokines/metabolism
MH  - Diabetes Complications/*enzymology/pathology/prevention & control
MH  - Diabetes Mellitus, Type 2/*enzymology/pathology
MH  - Fatty Liver/*enzymology/genetics/prevention & control
MH  - Heme Oxygenase (Decyclizing)/*metabolism
MH  - Hemin/pharmacology
MH  - Liver/*enzymology/pathology
MH  - Macrophages/enzymology/pathology
MH  - Male
MH  - Non-alcoholic Fatty Liver Disease
MH  - Obesity/complications/*enzymology/pathology
MH  - Rats
MH  - Rats, Zucker
PMC - PMC3829851
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2013/11/22 06:00
MHDA- 2014/07/08 06:00
PMCR- 2013/11/15
CRDT- 2013/11/22 06:00
PHST- 2013/06/06 00:00 [received]
PHST- 2013/09/24 00:00 [accepted]
PHST- 2013/11/22 06:00 [entrez]
PHST- 2013/11/22 06:00 [pubmed]
PHST- 2014/07/08 06:00 [medline]
PHST- 2013/11/15 00:00 [pmc-release]
AID - PONE-D-13-24693 [pii]
AID - 10.1371/journal.pone.0079270 [doi]
PST - epublish
SO  - PLoS One. 2013 Nov 15;8(11):e79270. doi: 10.1371/journal.pone.0079270. 
      eCollection 2013.