# Factors Controlling Metabolic Flux in the Liver

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $405,000

## Abstract

Project Summary:
Hepatocellular energy production is used to support biosynthetic, catabolic and futile pathways that
consume ATP or reducing equivalents. With the exception of proton leak and uncoupling, mitochondrial
function must match these requirements. This project is based on the scientific premise that hepatic insulin
resistance and obesity alter flux through energetically costly biosynthetic pathways. We propose that
changes in these pathways alter apparent mitochondrial function, resulting in increased oxidative damage in
liver. The project advances on our previous findings that (i) insulin resistance/NAFLD results in elevated
hepatic oxidative flux in animal models and humans; (ii) increased oxidative flux is associated with oxidative
stress and inflammation; (iii) suppressing gluconeogenesis prevented elevated oxidative metabolism,
oxidative stress and inflammation. This project tests the hypothesis that hepatic insulin resistance impinges
on mitochondrial metabolism by altering energetically costly biosynthetic pathways. Hence, seemingly
unrelated intermediary metabolism could have secondary effects on mitochondrial function and contribute to
factors like oxidative stress and inflammation in NAFLD. To test the hypothesis, we will use state-of-the-art
stable isotope tracer methods, NMR and MS to evaluate metabolic flux, and conditional gain/loss of function
mice to establish mechanism. Particular emphasis is placed on identifying the energetically dependent
pathways that account for changes in hepatic energy metabolism during insulin resistance, identifying which
signaling pathways contribute to these changes and determining whether preventing altered biosynthesis
during is sufficient to protect against oxidative damage during insulin resistance and fatty liver disease.

## Key facts

- **NIH application ID:** 10116367
- **Project number:** 5R01DK078184-13
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Shawn C Burgess
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,000
- **Award type:** 5
- **Project period:** 2008-02-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10116367

## Citation

> US National Institutes of Health, RePORTER application 10116367, Factors Controlling Metabolic Flux in the Liver (5R01DK078184-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10116367. Licensed CC0.

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