# Brain endoplasmic reticulum stress in non-alcoholic fatty liver disease

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2020 · $490,589

## Abstract

PROJECT SUMMARY:
Non-alcoholic fatty liver disease (NAFLD) affects 1 in 3 Americans and is a significant risk factor for type II
diabetes mellitus, insulin resistance and hepatic carcinoma. Characterized by excessive hepatic triglyceride
accumulation, the incidence of NAFLD is increasing exponentially - in line with the growing obesity epidemic.
There is mounting evidence that endoplasmic reticulum (ER) stress-induced transcription factor activation is
involved in the generation and maintenance of NAFLD. While mechanisms at the peripheral level are
important, changes in the autonomic nervous system are poorly understood yet crucial in the acute and long-
term regulation of liver metabolism. Our preliminary data have identified novel targets, mechanisms of action
and neuronal populations that play an essential role in NAFLD during diet-induced obesity in mice, including
within forebrain and hypothalamic regions, involving ER stress and activation of the transcription factor
activator protein-1 (AP-1). We also provide key evidence that elevations in sympathetic nervous system
outflow to the liver is an underlying component driving NAFLD. Using a combination of innovative imaging,
molecular, neuroanatomical and integrative physiological approaches, we will address the central hypothesis
that hepatic sympathetic overactivity due to ER stress-induced AP-1 activation in forebrain-hypothalamic
circuits is critical in driving the development of NAFLD. Our novel preliminary findings highlight ER stress in the
forebrain subfornical organ and hypothalamic paraventricular nucleus as a mediator of NAFLD during diet-
induced obesity in mice, and point to elevations in hepatic sympathetic nerve activity as a cause. Building upon
these findings, in Aim 1 we will comprehensively evaluate the role of forebrain and hypothalamic ER stress in
distinct neuronal populations in obesity-induced hepatic sympathetic overactivity and NAFLD development.
Long-lasting alterations in CNS function, including chronic activation of the sympathetic nervous system,
require changes in gene expression through regulation of inducible transcription factors. In line with this, in Aim
2, we will examine the role of ER stress in the activation of AP-1 in hypothalamic neurons during the
development of NAFLD. The functional role of brain AP-1 activation in the pathology of NAFLD will also be
examined. Dissecting the links between CNS ER stress and transcription factor activation in the control of
hepatic sympathetic outflow and NAFLD development has the potential to identify new therapeutic targets for
the treatment and prevention of this condition. Moreover, the combination of live animal molecular imaging,
brain site- and neuron subtype- specific manipulations, direct recording of central sympathetic outflow to the
liver, and comprehensive histological and molecular hepatic analysis provides a novel and integrative
approach to gain insight into NAFLD development.

## Key facts

- **NIH application ID:** 9985602
- **Project number:** 5R01DK117007-03
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Colin Neal Young
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,589
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985602

## Citation

> US National Institutes of Health, RePORTER application 9985602, Brain endoplasmic reticulum stress in non-alcoholic fatty liver disease (5R01DK117007-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9985602. Licensed CC0.

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