# Regulation of metabolic stress by the Snhg3 locus.

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2020 · $50,520

## Abstract

PROJECT SUMMARY/ABSTRACT
Excess fatty acids promote oxidative stress, cell death, and tissue dysfunction through a process called
lipotoxicity. In the liver, lipotoxicity contributes to nonalcoholic fatty liver disease, a disorder that can progress
from simple steatosis to nonalcoholic steatohepatitis (NASH), cirrhosis, or liver failure. The mechanisms that
connect lipid accumulation to cellular injury in NASH are not fully understood, but have been proposed to involve
lipid-induced oxidative stress. To uncover novel genes involved in lipotoxicity, our group conducted a promoter
trap mutagenesis screen in Chinese Hamster Ovary cells and selected for mutants resistant to palmitate-induced
cell death. Lines harboring loss-of-function mutations in the small nucleolar RNA hosting gene 3 (Snhg3) locus
were isolated and shown to be resistant to palmitate-induced oxidative stress, raising the possibility that this
locus may regulate the transition from steatosis to hepatitis in NASH. Snhg3 produces a long noncoding RNA,
SNHG3, and the U17 small nucleolar RNAs. I hypothesize that RNAs encoded by the Snhg3 locus regulate
lipotoxicity through interactions with other RNAs and proteins involved in cell metabolism, and that
Snhg3 regulates the pathogenesis of NASH. In Specific Aim 1, I will determine the RNA element(s) of Snhg3
that mediates lipotoxicity and identify its associated RNAs and proteins. This work will provide mechanistic
information regarding Snhg3 regulation of lipid-induced cell death. In Specific Aim 2, novel mouse models of
liver-specific Snhg3 knockout or overexpression will be used to examine the role of this locus in diet-induced
NASH. The overall goal of this research is to elucidate mechanisms of lipotoxicity in nonalcoholic fatty liver
disease, which could lead to new therapeutic strategies for targeting of noncoding RNAs that precipitate
metabolic stress.

## Key facts

- **NIH application ID:** 10006561
- **Project number:** 5F30DK120141-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Arthur Curtis Sletten
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2018-09-14 → 2022-07-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006561

## Citation

> US National Institutes of Health, RePORTER application 10006561, Regulation of metabolic stress by the Snhg3 locus. (5F30DK120141-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10006561. Licensed CC0.

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