# Metabolic Origins of Nonalcoholic Steatohepatitis

> **NIH NIH R01** · UNIV OF MARYLAND, COLLEGE PARK · 2020 · $342,000

## Abstract

Nonalcoholic steatohepatitis (NASH) is prevalent in over 70% of the obese and type II diabetes mellitus
(T2DM) patients and is a leading cause of liver transplantation. Hepatic insulin resistance and inflammation
mirror alterations in mitochondrial oxidative flux (beta-oxidation, tri-carboxylic acid [TCA] cycle and
mitochondrial respiration), in rodent models and humans with simple steatosis. This proposal will identify new
mechanisms leading to dysfunctional mitochondrial oxidative flux and development of NASH. The proposal will
test the hypothesis that the severity of hepatocyte inflammation and reactive oxygen species (ROS) generation
will be proportional to the rates of mitochondrial oxidative flux. Thus, attenuation of oxidative flux will provide a
promising strategy to alleviate inflammation and oxidative stress in NASH and T2DM. Aim 1 will test whether
altered mitochondrial oxidative flux during the transition from simple steatosis to NASH parallel an increase in
ROS production, inflammation and oxidative stress. This will be tested in a mouse model fed high fructose,
high trans-fat diet which gradually transitions from simple steatosis to NASH, closely resembling human
disease. Aim 2 will investigate a novel mechanism by which chronic elevation of branched chain amino acids
(BCAAs) during hepatic insulin resistance will disrupt mitochondrial oxidative flux and sustain lipogenesis. Aim
3 will utilize a novel mouse model with a clinically relevant polymorphism in the NADH dehydrogenase subunit
2 (mt-Nd2A) allele. This unique animal model will help identify whether the upregulated antioxidant defense
resulting from the beneficial effects of the mt-Nd2A allele will attenuate mitochondrial oxidative dysfunction in
NASH. State-of-the-art metabolic profiling techniques in nuclear magnetic resonance and mass spectrometry
will be combined with measures of ROS production and oxidative stress in liver. Direct measurements of
oxidative flux through the TCA cycle relative to ATP turnover in the liver will result in a novel index of
mitochondrial coupling efficiency, which will have high translational value for human studies. In conclusion,
identifying key mechanisms to attenuate mitochondrial oxidative flux will provide a better paradigm to treat
NASH and decrease unregulated gluconeogenesis in T2DM.

## Key facts

- **NIH application ID:** 9906207
- **Project number:** 5R01DK112865-04
- **Recipient organization:** UNIV OF MARYLAND, COLLEGE PARK
- **Principal Investigator:** Nishanth Sunny
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,000
- **Award type:** 5
- **Project period:** 2017-04-07 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906207

## Citation

> US National Institutes of Health, RePORTER application 9906207, Metabolic Origins of Nonalcoholic Steatohepatitis (5R01DK112865-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9906207. Licensed CC0.

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