# Project 1 - Yan Li, PhD

> **NIH NIH P20** · UNIVERSITY OF LOUISVILLE · 2021 · $218,400

## Abstract

Non-alcoholic steatohepatitis (NASH), a potential precursor of hepatocellular carcinoma (HCC), currently has no
FDA-approved treatment. Recent studies of fibroblast growth factor (FGF)19 and FGF21 on metabolism suggest
that endocrine FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic condi-
tions, including NASH. The Pegylated FGF21 (MS-986036) and FGF19 agonist (NGM282) have been studied
in clinical phase II trials. Our preliminary studies show that the lack of FGF21 accelerates steatohepatities pro-
gression and HCC transformation. Overexpression of FGF19/FGF receptor 4 significantly correlated with epithe-
lial cell adhesion molecule (EpCAM) as a marker of hepatic cancer stem cells within the fatty liver-steatosis-
cirrhosis-HCC sequence in patients. Recent studies indicated that FGF21 down-regulates the Th17-IL-17 axis,
suppresses NF-κB but activates p53 pathways, which are the critical anti-cancer mechanism(s). However, there
is no evidence demonstrating the specific anticancer effect of FGF21 on the NASH associated HCC. It is also
unknown whether FGF21 could negatively affect the Th17-IL-17 axis and the carcinogenetic signaling to abolish
the carcinogenetic transformation from NASH to HCC. Our central hypothesis is that FGF21 and FGF15/19
prevent NASH-HCC through, in turn, controlling lipolysis, clearing excessive FFAs, and inhibiting the IL-
17A signaling mediated inflammation and carcinogenesis. The hypothesis will be tested in the following
Specific Aims. Aim 1: Investigate lipid metabolic disorder and IL-17A mediated inflammation during NASH-HCC
transition. Establishing NASH-HCC mice to, 1) determine FFA pools (plasma, adipose, liver and feces) and FA
metabolites by metabolomics; 2) determine metabolic enzymes and components of IL-17A signaling by targeting
proteomics. Aim 2: Evaluate the efficacy of FGF21 (LY2405319) and FGF19 (NGM282) against NASH-HCC
transition. Administrating LY2405319/NGM282 in NASH-HCC mice to, 1) evaluate NASH score, HCC incidence,
hepatic injury and HCC lesion; 3) determine IL-17A-mediated inflammation/carcinogenesis and tumor-initiating
cells. Aim 3: Explore the preventive mechanism(s) of FGF21/FGF15/19 against NASH-HCC transition. Repro-
ducing NASH-HCC in FGF21 knockout (KO), FGF15KO and IL-17A mutation mice to investigate the feedback
loop of FGF21/FGF15/19-IL-17A on molecular target(s) linking to carcinogenetic pathways. The importance of
this proposal is: 1) to explore pharmacological use of FGF21/FGF15/19 against the NASH-HCC transition; and
2) to reveal therapeutic targets and mechanism(s), especially the IL-17 signaling linked carcinogenetic pathways,
during NASH-HCC transition.

## Key facts

- **NIH application ID:** 10026255
- **Project number:** 2P20GM113226-06
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Yan Li
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $218,400
- **Award type:** 2
- **Project period:** 2016-06-10 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10026255

## Citation

> US National Institutes of Health, RePORTER application 10026255, Project 1 - Yan Li, PhD (2P20GM113226-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10026255. Licensed CC0.

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