Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
AGER1 downregulation associates with fibrosis in nonalcoholic steatohepatitis and type 2 diabetes
Ali Dehnad, … , Mohammed Ali, Natalie J. Török
Ali Dehnad, … , Mohammed Ali, Natalie J. Török
Published July 13, 2020
Citation Information: J Clin Invest. 2020;130(8):4320-4330. https://doi.org/10.1172/JCI133051.
View: Text | PDF
Research Article Hepatology

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

  • Text
  • PDF
Abstract

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.

Authors

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

×

Figure 1

Hepatocyte RAGE is required for proinflammatory and fibrogenic signals in mice on a HiAD.

Options: View larger image (or click on image) Download as PowerPoint
Hepatocyte RAGE is required for proinflammatory and fibrogenic signals i...
(A) A HiAD induced a more significant increase in serum and liver AGEs than did a FFD. (B) WT and RageHepKO mice were placed on a HiAD for 14 weeks, and a group of mice received daily PM or vehicle (Tris-HCl). Liver AGEs increased in WT mice on a HiAD and decreased in these mice following PM treatment as well as in RageHepKO mice on a HiAD. Serum AGEs markedly increased with a HiAD, and this was attenuated by treatment with PM, whereas no increase was seen in RageHepKO mice on a HiAD. (C) H&E-stained images show inflammation and steatosis in HiAD-fed WT mice that improved after PM treatment and in HiAD-fed RageHepKO mice. NAS scores were 5–7 in the HiAD-fed WT mice, 1–2 in the HiAD+PM-treated mice, and 0–1 in the HiAD-fed RageHepKO mice. PSR staining shows fibrosis in WT mice on a HiAD, with improvement after PM treatment, and in RageHepKO mice on a HiAD. PSR staining was analyzed with ImageJ software. Collagen deposition was lower in the HiAD+PM and RageHepKO groups (n = 4 mice/group, 4 random ×20 fields/sample; data are presented as the percentage of PSR+ area/×20 field). Lipid peroxidation (4HNE) improved with PM treatment and in HiAD-fed RageHepKO mice. Scale bar: 100 μm. (D) Levels of ALT and inflammatory transcripts Mcp1, Tnfa, Il1b were reduced in PM-treated and RageHepKO mice. (E) Levels of fibrosis-related transcripts Col1a1, Tgfb, Mmp2 and hydroxyproline (OH-proline) decreased in PM-treated and RageHepKO mice. (F) CK19+ and SOX9+ RDCs were observed in the HiAD-fed mice. The number of positive cells was lower in the PM-treated mice and in RageHepKO mice on a HiAD. Scale bar: 100 μm. Images for FFD data are shown in Supplemental Figure 5. Data represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 1-way ANOVA followed by post hoc Tukey’s test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts