title: 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.affiliation: Department of Physiology, University of Saskatchewan College of Medicine, Saskatoon, Saskatchewan, Canada.
authors.forename: Tatiana Ntube
authors.initials: TN
authors.lastname: Salley
authors.forename: Manish
authors.initials: M
authors.lastname: Mishra
authors.forename: Shuchita
authors.initials: S
authors.lastname: Tiwari
authors.forename: Ashok
authors.initials: A
authors.lastname: Jadhav
authors.forename: Joseph Fomusi
authors.initials: JF
authors.lastname: Ndisang
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D048909:Diabetes Complications / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000473:pathology; D005234:Fatty Liver / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D051381:Rats; D011924:Rats, Zucker
chemical_list: D016207:Cytokines; D006427:Hemin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat