Advanced glycation end products induce liver injury in non-alcoholic steatohepatitis (NASH) via hepatocyte NOX4
Year: 2016
Type: article
Abstract: NASH is leading cause of liver injury, and patients with typeII DM are prone for aggressive disease. ROS play a key role in progression, and NOX4 is an important source of H2O2; but the mechanisms linking AGEs exposure to NOX4/RAGE signaling have been undefined. We hypothesized that circulating AGEs activate hepatocyte NOX4 via RAGE leading to progressive injury. RAGE was studied in patients with steatosis, or NASH/ DM; in hepatocyte-specific NOX4KOs (NOX4hepKO) and fl/fl controls following fast food diet (FFD). Liver AGEs and expression of detoxifying enzyme AGER1 were assessed. JNK1 phosphorylation, ROS, apoptosis were evaluated, and fibrosis assessed (fibrogenic transcripts, hydroxyl proline). In vitro, NOX4 promoter studies were done after AGEs exposure. Results: RAGE was induced in patients with DM/NASH (p<0.05), and in mice on FFD. In NOX4hepKO mice RAGE was downregulated (p<0.05), and ROS, lipid peroxidation, CHOP and JNK1 activation were attenuated, fibrosis improved (p<0.05). AGER1 was significantly lower in mice on FFD. BSA/AGEs induced NOX4 promoter activity/H2O2 release. Conclusion: AGEs-induced NOX4/H2O2 in hepatocytes leads to stress signals and downregulation of AGER1 further promotes liver fibrosis. Targeting AGEs/RAGE could thus be beneficial to improve outcomes.
Authors: Jiang, Joy, Sato, Ai, Brandes, Ralph, Torok, Natalie
Institution: University of California, Davis
Language: English
Subfield: Clinical Biochemistry
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2486559121