# Mechanism of GDNF regulation of Hepatic Steatosis

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## 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. Hepatic steatosis is a component of
NAFLD, wherein there is accumulation of triglycerides in the liver. Recently we published that GDNF
transgenic mice fed a high fat diet are protected from obesity and the development of hepatic steatosis despite
similar food intake and physical activity. GDNF transgenic mice over express GDNF in glia under the GFAP
promoter (GDNF-tg) GDNF (expressed in glia) and its receptors, cRET and GFR-1 are expressed in human
and murine hepatocytes. Thus, GDNF present in the liver can act locally on the hepatocytes. GDNF-tg mice
demonstrate enhanced energy utilization assessed by indirect calorimetry. Having established a role for
GDNF in preventing hepatic steatosis we recently examined the role of GDNF in preventing liver injury. Our
preliminary data demonstrate novel effects of GDNF on the liver that include: (i) GDNF prevents HFD-induced
liver injury (ii) GDNF-tg mice fed a HFD have increased hepatic levels of autophagy; and (iii) Hepatocytes
treated with GDNF have improved mitochondrial function as seen by increased basal and mitochondrial
respiration The mechanisms 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
autophagy and by improving mitochondrial function leading to increased hepatocyte survival. GDNF can
increase lipid droplet turnover, fat oxidation and oxidative phosphorylation in hepatic cells through the
autophagic pathway. In this proposal we will establish the mechanism of GDNF regulation of hepatocyte
autophagy and improved mitochondrial function. Currently there are no FDA approved drugs for the treatment
of hepatic steatosis. We have identified a novel neurotrophic factor GDNF that decreases both hepatic
steatosis and injury through enhancing autophagy and mitochondrial function. Using both genetic and
pharmacological approaches we will define the role of GDNF in inducing autophagy to lead to oxidative lipid
metabolism, fat reduction and reduced hepatic injury. We propose the following interrelated, but independently
achievable aims: Specific Aim 1: To determine if the mechanism by which GDNF decreases hepatocyte lipid
accumulation is through enhanced autophagy mediated lipolysis mediated by suppression of mTOR signaling.
Preliminary data indicate that GDNF is a potent inducer of autophagy. We will establish whether autophagy
mediates the GDNF-induced reduction in cellular lipid stores by studies of overexpression and knockdown of
autophagy related genes. Preliminary data indicate that GDNF suppresses pmTOR signaling which is the
prime inhibitory pathway of autophagy. We will determine the mechanism of GDNF up regulation of autophagy
focusing on the mTOR pathway. WT and GDNF-tg mice will be fed a high f...

## Key facts

- **NIH application ID:** 9898210
- **Project number:** 5I01BX000136-11
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Shanthi K Srinivasan
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898210

## Citation

> US National Institutes of Health, RePORTER application 9898210, Mechanism of GDNF regulation of Hepatic Steatosis (5I01BX000136-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898210. Licensed CC0.

---

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