Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Role of hepatic NADPH oxidase 4 in the development of obesity and liver disease. (#175)

Supreet Kaur 1 , Melanie Tran 2 , Garron Dodd 1 , Junichi Sadoshima 3 , Matthew Watt 1 , Tony Tiganis 1
  1. Monash University, Clayton, VIC, Australia
  2. University of Connecticut, Storrs, Connecticut, United States
  3. Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, New Jersey, United States

Reactive oxygen species (ROS) have long been suspected as detrimental to the progression of various human diseases including type 2 diabetes, liver steatosis, non-alcoholic steatohepatitis (NASH) and liver cirrhosis. An excess of ROS (oxidative stress) caused by an imbalance in metabolism, may be a common underlying pathogenic mechanism in such diseases. NADPH oxidases are multi-subunit transmembrane enzyme complexes that generate superoxide (O.-2) or hydrogen peroxide (H2O2) from molecular oxygen using NADPH as an electron donor (Bedard K et al., 2007). Our aim was to examine the contribution of ROS generated by NADPH oxidase 4 (NOX4) in hepatocytes to liver pathophysiology. We investigated the role of hepatocyte NOX4 in the regulation of glucose homeostasis and in the progression of obesity-induced steatosis and NASH. Mice with hepatocyte-specific deletion of NOX4 (Alb-Cre;Nox4fl/fl) and control mice (Nox4fl/fl) were fed 1) a chow diet, 2) a 23% high fat diet (12 weeks) that promotes obesity and NAFLD; 3) a choline-deficient 23% high fat diet (CD-HFD) that promotes obesity and NASH; or 4) a choline deficient amino-acid defined diet (CDAA) that promotes obesity independent NASH; and the overall impact on body weight, oxidative stress, insulin sensitivity, glucose homeostasis and steatosis/NASH assessed. Chow-fed Alb-Cre;Nox4fl/fl mice did not exhibit any alterations in body composition or energy expenditure but showed improved insulin sensitivity. High fat fed Alb-Cre;Nox4fl/fl mice had increased body weight, adiposity, steatosis, liver fibrosis and decreased insulin sensitivity. Alb-Cre;Nox4fl/fl mice also exhibited increased hepatic tri-glycerides, plasma insulin levels and hepatic lipogenic gene expression. NOX4 deficiency showed increased inflammation and fibrosis in CDAA-fed mice. NOX4 deficiency did not alter the development of NASH in CD-HFD fed mice. NOX4 in hepatocytes plays an important role in promoting insulin sensitivity and preventing diet induced obesity and hepatosteatosis. This work highlights the importance of NOX4 derived ROS in liver pathophysiology.