Introduction: Nonalcoholic fatty liver (NAFLD) occurs in a setting of high fat diets, insulin resistance, obesity and dyslipidemia. Individuals with NAFLD have an increased risk of developing metabolic syndrome. Heme oxygenase-1 (HMOX1), a major cytoprotective enzyme, attenuates oxidative stress and obesity and increases insulin sensitivity. The antioxidant effect of HMOX1 is due to an increase in ferritin, and bilirubin and a decrease in heme, a pro-oxidant. The aim of this study was to examine the role of increased hepatic HMOX activity in decreasing steatosis, adiposity and vascular dysfunction and to determine the mechanism underlying these metabolic changes in obese mice.
Methods: Obese mice were administered cobalt protoporphyrin (CoPP) and HMOX activity inhibitor stannous mesoporphyrin (SnMP) for 6 weeks. Blood pressure, body weight and blood glucose levels were measured in all the groups. Glycogen content, hepatic fibrosis, heme levels, fatty acid synthase (FAS) and lipid droplet size in liver were also assessed.
Results: CoPP administration increased hepatic HMOX1 protein levels and HMOX activity, decreased blood pressure, body weight, blood glucose levels, hepatic heme content (p<0.05) as compared to obese mice. Our results also showed that HMOX1 induction causes a significant decrease in lipid steatosis ( lipid droplet size and FAS levels; p<0.01) as compared to obese mice. Densitometry analysis showed increased expression of PPARα and Glut 1 along with decreased expression of PGC1α in hepatic tissue. These beneficial effects were reversed by administration of SnMP.
Conclusion: This novel study demonstrates the role of hepatic HMOX1 in attenuating the fatty liver and metabolic homeostasis by decreasing PGC1α and heme content and enhancing glycogen levels. Pharmacological agents that increase HMOX1 levels or gene targeting of HMOX1 offer a promising therapeutic target for NAFLD and suggest the existence of a significant link between the heme-HMOX system and the extent and severity of heme-dependent fatty liver.