Terry D. Hinds1, Komal Sodhi1, Charles Meadows1, Larisa Fedorova, Nitin Puri, Dong Hyun Kim1, Stephen J. Peterson2, Joseph I. Shapiro1, Nader G. Abraham1,3, Attallah Kappas3
1Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA
2Department of Medicine New York Methodist‐Weill Cornell Medical College New York New York USA
3Laboratory of Pharmacology The Rockefeller University New York New York USA
Tóm tắt
ObjectiveObese leptin deficient (ob/ob) mice are a model of adiposity that displays increased levels of fat, glucose, and liver lipids. Our hypothesis is that HO‐1 overexpression ameliorates fatty liver development.MethodsObese mice were administered cobalt protoporphyrin (CoPP) and stannic mesoporphyrin (SnMP) for 6 weeks. Heme, HO‐1, HO activity, PGC1α, FGF21, glycogen content, and lipogenesis were assessed.ResultsCoPP administration increased hepatic HO‐1 protein levels and HO activity, decreased hepatic heme, body weight gain, glucose levels, and resulted in decreased steatosis. Increased levels of HO‐1 produced a decrease in lipid droplet size, Fatty acid synthase (FAS) levels involving recruitment of FGF21, PPARα, and Glut 1. These beneficial effects were reversed by inhibition of HO activity.ConclusionIncreased levels of HO‐1 and HO activity reduced the levels of obesity by reducing hepatic heme and lipid accumulation. These changes were manifested by decreases in cellular heme, increases in FGF21, glycogen content, and fatty liver. The beneficial effect of HO‐1 induction results from an increase in PPARα and FGF21 levels and a decrease in PGC1α, levels they were reversed by SnMP. Low levels of HO‐1 and HO activity are responsible for fatty liver.
