# Mechanism of GDNF Regulation of Hepatic Steatosis

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2024 · —

## Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease in veterans and its
prevalence continues to increase, with the growing obesity epidemic. Currently more than 25% of our veterans
are obese and a larger number are overweight. In this proposal, we will examine the pleiotropic effects of Glial
Derived Neurotrophic Factor (GDNF) on hepatocytes. We have demonstrated that GDNF transgenic (GDNF-
Tg) mice fed a high fat diet are protected from obesity and the development of hepatic steatosis despite similar
food intake and physical activity. GDNF-Tg mice overexpress GDNF under the control of the GFAP promoter
expressed in glia and stellate cells. GDNF and its receptor GFRα−1 are expressed in human and murine
hepatocytes. Thus, GDNF present in the liver can act locally on the hepatocytes. We recently demonstrated
that GDNF can enhance autophagy and prevent liver injury. Our preliminary data demonstrate novel effects of
GDNF on the liver that include: (i) Human liver tissue from patients with steatosis and fibrosis have reduced
GDNF expression (ii) Western diet (WD)-fed mice have reduced level of Sirt3 and this is ameliorated in GDNF-
Tg mice fed a WD; (iii) Human hepatocytes treated with GDNF have increased mitophagy. (iv) GDNF prevents
apoptosis in primary human hepatocytes. The signaling pathway for these potentially beneficial effects of
GDNF have yet to be explored. We hypothesize that the mechanism of GDNF prevention of hepatic injury is
through promoting hepatocyte Sirt3 signaling, subsequent improved mitochondrial function leading to
increased hepatocyte survival. Using both genetic and pharmacological approaches we will define the role of
GDNF in inducing mitophagy to lead to improved mitochondrial function, fat reduction and reduced hepatic
injury. To test the hypothesis and further investigate the underlying mechanism(s) of GDNF regulation of
hepatic steatosis, we propose the following interrelated, but independently achievable aims: Specific Aim 1:
To determine the mechanism of GDNF regulation of Sirt3 Preliminary data indicate that GDNF is a potent
inducer of Sirt3 in vivo and in vitro. We have demonstrated that GDNF can activate the ERK signaling pathway
in hepatocytes through its receptor GFRα1. We will establish if the mechanism of GDNF regulation of Sirt3 is
through the GFRα1-ERK-CREB-PGC-1α pathway. WT and GDNF-Tg mice will be fed a Western diet together
with fructose and glucose added in drinking water (WD/FG) for 16 weeks and ERK-CREB-PGC-1α-Sirt3
pathway assessed in hepatocytes. In vitro the necessity and sufficiency of ERK-CREB-PGC-1α in the GDNF
regulation of Sirt3 expression will be determined using gene knock down and overexpression strategies.
Specific Aim 2: To examine the role of mitochondrial function and mitophagy in GDNF-mediated
hepatocyte survival. Our preliminary data demonstrate that GDNF increases mitochondrial function and
mitophagy in hepatocytes. We will establish the role of GDNF in...

## Key facts

- **NIH application ID:** 10726567
- **Project number:** 5I01BX000136-14
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Shanthi K Srinivasan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2025-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10726567

## Citation

> US National Institutes of Health, RePORTER application 10726567, Mechanism of GDNF Regulation of Hepatic Steatosis (5I01BX000136-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10726567. Licensed CC0.

---

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