Author/Authors :
Sacerdoti, David Departments of Medicine - Pharmacology and Gastroenterology - New York Medical College - Valhalla - NY 10595, USA - Department of Medicine - University of Padova - Padova, Italy , Singh, Shailendra P. Departments of Medicine - Pharmacology and Gastroenterology - New York Medical College - Valhalla - NY 10595, USA , Schragenheim, Joseph Departments of Medicine - Pharmacology and Gastroenterology - New York Medical College - Valhalla - NY 10595, USA , Bellner, Lars Departments of Medicine - Pharmacology and Gastroenterology - New York Medical College - Valhalla - NY 10595, USA , Vanella, Luca Department of Drug Science - University of Catania - Catania, Italy , Raffaele, Marco Department of Drug Science - University of Catania - Catania, Italy , Meissner, Aliza Departments of Medicine - Pharmacology and Gastroenterology - New York Medical College - Valhalla - NY 10595, USA , Grant, Ilana Departments of Medicine - Pharmacology and Gastroenterology - New York Medical College - Valhalla - NY 10595, USA , Favero, Gaia Anatomy and Physiopathology Division - Department of Clinical and Experimental Sciences - University of Brescia - Brescia, Italy , Rezzani, Rita Anatomy and Physiopathology Division - Department of Clinical and Experimental Sciences - University of Brescia - Brescia, Italy , Rodella, Luigi F. Anatomy and Physiopathology Division - Department of Clinical and Experimental Sciences - University of Brescia - Brescia, Italy , Bamshad, David Departments of Medicine - Pharmacology and Gastroenterology - New York Medical College - Valhalla - NY 10595, USA , Lebovics, Edward Departments of Medicine - Pharmacology and Gastroenterology - New York Medical College - Valhalla - NY 10595, USA , Abraham, Nader G. Marshall University - Joan C. Edwards School of Medicine - Huntington - WV 25701, USA - Departments of Medicine - Pharmacology and Gastroenterology - New York Medical College - Valhalla - NY 10595, USA
Abstract :
Aim. Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and
lipotoxicity. We hypothesize that an increase in the infammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO1) levels in adipose and hepatic tissue, resulting in the development of NASH in obese mice. Methods. Mice were fed a high
fat diet (HFD) and obese animals were administered an HO-1 inducer with or without an inhibitor of HO activity to examine
levels of adipose-derived NOV and possible links between increased synthesis of infammatory adipokines and hepatic pathology.
Results. NASH mice displayed decreased HO-1 levels and HO activity, increased levels of hepatic heme, NOV, MMP2, hepcidin,
and increased NAS scores and hepatic fbrosis. Increased HO-1 levels are associated with a decrease in NOV, improved hepatic NAS
score, ameliorated fbrosis, and increases in mitochondrial integrity and insulin receptor phosphorylation. Adipose tissue function
is disrupted in obesity as evidenced by an increase in proinfammatory molecules such as NOV and a decrease in adiponectin.
Importantly, increased HO-1 levels are associated with a decrease of NOV, increased adiponectin levels, and increased levels of
thermogenic and mitochondrial signaling associated genes in adipose tissue. Conclusions. Tese results suggest that the metabolic
abnormalities in NASH are driven by decreased levels of hepatic HO-1 that is associated with an increase in the adipose-derived
proinfammatory adipokine NOV in our obese mouse model of NASH. Concurrently, induction of HO-1 provides protection
against insulin resistance as seen by increased insulin receptor phosphorylation. Pharmacological increases in HO-1 associated
with decreases in NOV may ofer a potential therapeutic approach in preventing fbrosis, mitochondrial dysfunction, and the development of NASH.
