Journal Article

AGER1 downregulation associates with fibrosis in nonalcoholic steatohepatitis and type 2 diabetes

Jiang, Joy X., Li, Yuan, Török, Natalie J., Das, Suvarthi, Olson, Kristin A., Dehnad, Ali, Fan, Weiguo, Charville, Gregory W., Ali, Mohammed, Fish, Sarah R., Mozes, Gergely, Wong, Kimberly A.

2020

Overview

Type 2 diabetes is clinically associated with progressive necroinflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Advanced glycation end-products (AGEs) accumulate during prolonged hyperglycemia, but the mechanistic pathways that lead to accelerated liver fibrosis have not been well defined. In this study, we show that the AGEs clearance receptor AGER1 was downregulated in patients with NASH and diabetes and in our NASH models, whereas the proinflammatory receptor RAGE was induced. These findings were associated with necroinflammatory, fibrogenic, and pro-oxidant activity via the NADPH oxidase 4. Inhibition of AGEs or RAGE deletion in hepatocytes in vivo reversed these effects. We demonstrate that dysregulation of NRF2 by neddylation of cullin 3 was linked to AGER1 downregulation and that induction of NRF2 using an adeno-associated virus-mediated approach in hepatocytes in vivo reversed AGER1 downregulation, lowered the level of AGEs, and improved proinflammatory and fibrogenic responses in mice on a high AGEs diet. In patients with NASH and diabetes or insulin resistance, low AGER1 levels were associated with hepatocyte ballooning degeneration and ductular reaction. Collectively, prolonged exposure to AGEs in the liver promotes an AGER1/RAGE imbalance and consequent redox, inflammatory, and fibrogenic activity in NASH.

• Publisher: American Society for Clinical Investigation
• Subject: Advanced glycosylation end products / Age / Animals / Ascorbic Acid / Biomedical research / Cholecalciferol / Cullin / Degeneration / Dehydroepiandrosterone - analogs & derivatives / Diabetes / Diabetes mellitus (non-insulin dependent) / Diabetes Mellitus, Type 2 - genetics / Diabetes Mellitus, Type 2 - metabolism / Diabetes Mellitus, Type 2 - pathology / Diet / Disease Models, Animal / Down-Regulation / Fibrosis / Glycosylation / Hepatocytes / Hepatocytes - metabolism / Hepatocytes - pathology / Hyperglycemia / Inflammation / Insulin / Insulin resistance / Lipid peroxidation / Liver / Liver Cirrhosis - genetics / Liver Cirrhosis - metabolism / Liver Cirrhosis - pathology / Liver diseases / Mice / Mice, Knockout / NAD(P)H oxidase / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - metabolism / Nicotinic Acids / Non-alcoholic Fatty Liver Disease - genetics / Non-alcoholic Fatty Liver Disease - metabolism / Non-alcoholic Fatty Liver Disease - pathology / Oxidants / Oxidases / Phosphorylation / Plant Extracts / Receptor for Advanced Glycation End Products - biosynthesis / Receptor for Advanced Glycation End Products - genetics / Rodents / Type 2 diabetes