# The role of AEG-1 in NASH and NASH-HCC

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2024 · $577,461

## Abstract

Summary
Nonalcoholic steatohepatitis (NASH), the most common cause of chronic liver disease in the Western world
and a major global health problem, leads to cirrhosis and hepatocellular carcinoma (HCC). The lack of an
optimum therapy mandates better understanding of the molecular pathogenesis of NASH, identification of
regulatory molecules and development of targeted therapeutic approaches. Studies, supported by previous
cycle of this renewal application, unraveled a novel role of the oncogene Astrocyte elevated gene-1/Metadherin
(AEG-1/MTDH) in promoting NASH. AEG-1 induces steatosis by inhibiting PPARα, hence fatty acid β-oxidation
(FAO), and promoting translation of fatty acid synthesizing enzymes thus augmenting de novo lipogenesis
(DNL). Additionally, AEG-1 activates NF-κB, a master regulator of inflammation. Thus AEG-1 plays a key role
in NASH and NASH-HCC. We established the therapeutic efficacy of a hepatocyte-targeted nanoparticle
delivering AEG-1 siRNA to inhibit HFD-induced NASH in mice. Macrophages play a pivotal role in the
pathogenesis of NASH by regulating the functions of adipocytes and hepatocytes. We recently documented
that AEG-1 plays a vital role in regulating macrophage activation and mice with deletion of AEG-1 in myeloid
cells (AEG-1∆MAC) are profoundly resistant to N-nitrosodiethylamine (DEN)-induced inflammatory HCC. Our
preliminary studies now document that AEG-1∆MAC mice are also resistant to HFD-induced NASH, and identify
that a novel post-translational modification, cysteine palmitoylation, is required for protein translation and NF-
κB activation functions of AEG-1. These observations allow us to hypothesize that macrophage AEG-1
promotes NASH by regulating adipocytes and hepatocytes, cysteine palmitoylation regulates AEG-1 functions
which contribute to NASH development, and targeted inhibition of AEG-1 in macrophages and hepatocytes
might be an effective therapeutic intervention for NASH. Experiments using relevant mouse models and human
cells will be performed to address these hypotheses. Our proposed studies will unravel a novel role of AEG-1
in macrophages and a novel post-translational modification regulating AEG-1 function. Multiple clinical trials
document efficacy of inhibiting expression of genes in the liver by RNA interference (RNAi) strategy in a variety
of diseases thereby establishing potential application of this strategy to manage NASH in the clinics. Our
proposed studies thus have important mechanistic and translational significance.

## Key facts

- **NIH application ID:** 10760282
- **Project number:** 5R01DK107451-07
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Devanand Sarkar
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $577,461
- **Award type:** 5
- **Project period:** 2016-07-25 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10760282

## Citation

> US National Institutes of Health, RePORTER application 10760282, The role of AEG-1 in NASH and NASH-HCC (5R01DK107451-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10760282. Licensed CC0.

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