# Fibroblast growth factor 1 prevents hyperlipidemia and atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2022 · $553,582

## Abstract

Atherosclerosis is a narrowing of arteries caused by plaque buildup. Dyslipidemia, especially elevated low-
density lipoprotein cholesterol, is a major risk factor for atherosclerotic plaque formation. Current therapies for
atherosclerosis focus on lowering cholesterol. However, conventional lipid lowering therapies (such as statins)
are associated with obvious side effects. Developing more specific and efficient treatments are needed.
Fibroblast growth factor 1 (FGF1) has been widely studied for its therapeutic benefits in cardiovascular disorders
primary utilization of its mitogenic functions. Recently, FGF1 was shown to exert an unexpected metabolic activity
by regulating adipose remodeling and glucose homeostasis, demonstrating a potential for treatment of metabolic
syndrome. However, wild-type FGF1 (FGF1WT) induced hyperproliferation can lead to increased tumorigenic risk;
this becomes the primary obstacle for its widespread application. To reduce this risk, we recently engineered a
partial FGF1 agonist carrying triple mutations of the heparin-binding sites (FGF1ΔHBS), which abolished
proliferative potential, but maintains full FGF1WT metabolic activity. Notably, chronic treatment of db/db mice with
FGF1ΔHBS almost completely reversed diabetes-associated NAFLD. These findings suggest that FGF1ΔHBS is a
potentially safe and efficient therapeutic approach for treatment of metabolic syndrome.
Although characterization of the metabolic functions of FGF1 is ongoing, little is known about its roles in
atherosclerosis. A small case observation found an increased FGF1 expression in neovascularized and
macrophage-rich regions of plaque, implying a potential pathological role of FGF1 in human atherogenesis.
However, whether and how FGF1 plays beneficial or detrimental roles in atherogenesis remain unexplored. We
recently examined the impact of FGF1 administration on the pathogenesis of atherosclerosis in ApoE-KO mice
and found that FGF1ΔHBS markedly ameliorated atherosclerotic phenotypes without significant proliferative
potential in liver. Furthermore, FGF1 treatment reduced cholesterol levels in the blood, liver and intestine, but
increased cholesterol contents in feces. These preliminary data indicate that FGF1 regulation of cholesterol
homeostasis in both liver and intestine is responsible for its protection from atherosclerosis. The liver is a major
site for cholesterol biosynthesis while the intestine maintains cholesterol homeostasis by mediating intestinal
absorption of dietary and biliary cholesterol. Therefore, we hypothesize that non-mitogenic variant FGF1ΔHBS
prevents atherosclerosis by inhibiting hepatic cholesterol synthesis and suppressing intestinal
cholesterol absorption without risks of hyperproliferation. We will test the hypothesis in three specific aims:
1) Determine the roles of FGF1 in the development of atherosclerosis; 2) Determine the effects and mechanism
of FGF1 on hepatic cholesterol biosynthesis; 3) Determine the effects ...

## Key facts

- **NIH application ID:** 10345440
- **Project number:** 1R01HL160927-01
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Yi Tan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $553,582
- **Award type:** 1
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10345440

## Citation

> US National Institutes of Health, RePORTER application 10345440, Fibroblast growth factor 1 prevents hyperlipidemia and atherosclerosis (1R01HL160927-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10345440. Licensed CC0.

---

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