The Interactive Effects of Iron and Receptor for Advanced Glycation End Products (RAGE) on Non-alcoholic Fatty Liver Disease (NAFLD)

Calorie restriction is the common strategy for non-alcoholic fatty liver disease (NAFLD) treatment. However, the role of dietary factors in the development and progression of NAFLD are still unclear. Defining the mechanisms underlying diet-induced induction and maintenance of progressive NAFLD is thus of critical importance. The significance of this proposal lies in the clinical observation that “dysmetabolic iron overload syndrome” is a common disorder in NAFLD and glycotoxins may modify iron molecules and induce liver injury by activating the receptors for advanced glycation end products (RAGE). The objective of this proposal is to investigate the interactive effects between iron and RAGE pathways on NAFLD progression. This will be accomplished through experiments involving: (1) a cross-sectional study investigating the association between dietary advanced glycation end products (AGEs) intake levels, iron biomarkers (serum ferritin, CD163, hepcidin), RAGE and RAGE ligands (AGEs and high-mobility group box 1(HMGB1)) in NAFLD patients, (2) proof of concept experiment in high fat induced NAFLD mouse model to characterize the role of fat-to-iron induced AGEs on RAGE-mediated oxidative stress and progression from steatohepatitis to fibrosis. (3) a retrospective examination of hepatic iron, iron biomarkers , RAGE and RAGE ligands in biopsy-proven NAFLD specimen. This study will advance our current knowledge on how to treat NAFLD patients and to provide better care for NAFLD management in practice.