# Inhibition of EGF Receptor Prevents and Reverses Non-Alcoholic Fatty Liver Disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2021 · $473,996

## Abstract

ABSTRACT
In the last two decades, there has been an increased appreciation of a long-term threat, that of non-alcoholic
fatty liver disease (NAFLD), evolving into non-alcoholic steatohepatitis (NASH), which can further advance into
cirrhosis and hepatocellular carcinoma (HCC). Treatment of NAFLD and NASH is primarily through attempts at
nutritional modification, often unsuccessful due to poor compliance and socioeconomic factors. There is
currently no accepted single-agent pharmacologic treatment for NAFLD. The current proposal is based on
findings from our work on liver regeneration, in which we discovered a unique role for EGFR for control of
steatosis in replicating hepatocytes. We have now extended these studies in mice fed a high fat diet
supplemented with fructose in the drinking water (“Fast Food Diet”, FFD). We found that in mice on FFD,
concurrent EGFR inhibition completely prevented and eliminated any fat deposition in hepatocytes.
Furthermore, EGFR inhibition reversed severe hepatocyte steatosis established after FFD feeding for 4
months. Detail analysis of the mechanisms revealed widespread effects of EGFR inhibition on multiple
transcription factors related to lipid metabolism and subsequent consequences to specific enzymes associated
with lipid biosynthesis and degradation. No such findings occur when signaling from the other of the two
hepatocyte-mitogenic receptor tyrosine kinases, MET (the HGF receptor), was eliminated. The purpose of this
proposal is to explore translational applications of this finding. This will be done by exploring effects of EGFR
inhibitors established in human pharmacology. In addition, we will conduct parallel analysis between EGFR
and MET signaling inhibition on their effects of NAFLD, aiming to uncover specific pathways unique to EGFR
that may reveal new pharmacologic approaches more focused than the inhibition of the entire EGFR signaling
with its potentially adverse complications. In parallel studies, we will also use available human NAFLD/NASH
tissue material available in the Biorepository of our Pittsburgh Liver research Center (PLRC). This material will
be used under the established rules of IRB obtained by PLRC for such studies. We will explore activation of
EGFR dependent pathways and will correlate with the histology of NAFLD/NASH. A serious complication of
progression of NAFLD to NASH is development of fibrosis. We have uncovered EGFR-controlled signaling
molecules in steatotic hepatocytes, which have been associated with activation of hepatic stellate cells and
enhanced production of collagens. These also offer opportunities for selective pharmacology for fibrosis and
their relevance will be assessed in the studies proposed.

## Key facts

- **NIH application ID:** 10117752
- **Project number:** 1R01DK122990-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** GEORGE K MICHALOPOULOS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $473,996
- **Award type:** 1
- **Project period:** 2021-02-03 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117752

## Citation

> US National Institutes of Health, RePORTER application 10117752, Inhibition of EGF Receptor Prevents and Reverses Non-Alcoholic Fatty Liver Disease (1R01DK122990-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10117752. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*