The heme oxygenase system rescues hepatic deterioration in the condition of obesity co-morbid with type-2 diabetes.

Abstract

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-α, IL-6, IL-1β, macrophage-inflammatory-protein-1α (MIP-1α) 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-β1, 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-α, IL-6, IL-1β, MIP-1α and MCP-1 are among the multifaceted mechanisms by which hemin restore hepatic morphology.

• Authors: Tatiana Ntube Salley, Manish Mishra, Shuchita Tiwari, Ashok Jadhav, Joseph Fomusi Ndisang
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e79270 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24260182 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Hemin
• Heme Oxygenase (Decyclizing)
• Hmox1 protein, rat

Topics

• Animals
• Cytokines (metabolism)
• Diabetes Complications (enzymology, pathology, prevention & control)
• Diabetes Mellitus, Type 2 (enzymology, pathology)
• Fatty Liver (enzymology, genetics, prevention & control)
• Heme Oxygenase (Decyclizing) (metabolism)
• Hemin (pharmacology)
• Liver (enzymology, pathology)
• Macrophages (enzymology, pathology)
• Male
• Non-alcoholic Fatty Liver Disease
• Obesity (complications, enzymology, pathology)
• Rats
• Rats, Zucker