# A METABOLIC BIOMARKER OF HEPATIC NADH/NAD+ RATIO

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $172,600

## Abstract

PROJECT ABSTRACT
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world, and is an
increasing cause of significant morbidity and mortality. Despite its growing impact on global health there are
currently no FDA-approved therapies for treatment. While the pathophysiology of NAFLD is complex,
increasing evidence supports a direct role of alterations in hepatic NADH/NAD+ levels. However, testing the
role of NADH/NAD+ in hepatic physiology is challenging given the limitations of existing tools with which to
manipulate it in a precise manner, and the lack of circulating biomarkers for NADH/NAD+ which, as unstable
intracellular metabolites, would be impractical to measure in most clinical and human research settings.
The Mootha lab has developed a genetically encoded metabolic tool, called LbNOX, to directly and precisely
manipulate cellular NADH/NAD+ in different tissues and cellular compartments. In preliminary work, I have
used this tool both in vitro and in vivo to identify that a circulating metabolite, α-hydroxybutyrate (αHB) is
sensitive to alterations in hepatic NADH/NAD+. αHB, has previously been shown to be a biomarker of insulin
resistance and sensitive to polymorphisms in the gene GCKR, which in turn has been associated with NAFLD.
Our preliminary work also shows LbNOX improves hepatic insulin resistance in vivo, and that GCKR influences
hepatocyte NADH/NAD+. These findings link GCKR, NAFLD, αHB, and hepatic NADH/NAD+. The central
hypothesis of this proposal is that αHB is a circulating biomarker of hepatic NADH/NAD+ which is
causally linked to hepatic insulin resistance and steatosis, and that genetic modulators of hepatic
NADH/NAD+ influence hepatic steatosis and insulin resistance
In this proposal, I will use a combination of in vitro and in vivo hepatic LbNOX expression to further define the
causal connection between hepatic insulin resistance, hepatic steatosis, and hepatic NADH/NAD+. I will define
the mechanism by which LbNOX improves hepatic insulin resistance, and the mechanism by which GCKR
influences hepatic NADH/NAD+.
I am a clinical and research hepatologist dedicated to a research career as a physician scientist specializing in
metabolic aspects of liver disease. The proposed research plan will allow me to develop new knowledge and
expertise in metabolism, metabolomics, and hepatic physiology, and provide experience with animal models of
chronic liver disease. Throughout the proposed research I will be guided by a formal research advisory
committee comprised of outstanding mentors and experts in metabolism, NAFLD, and hepatic physiology, all in
the setting of a stellar research environment comprised of MGH, the Broad Institute, and affiliated institutions.
The research proposed, along with the guidance of my mentors and collaborators in this research, will help
ensure my successful transition to scientific independence.

## Key facts

- **NIH application ID:** 9986789
- **Project number:** 5K08DK115881-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Russell Paul Goodman
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $172,600
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986789

## Citation

> US National Institutes of Health, RePORTER application 9986789, A METABOLIC BIOMARKER OF HEPATIC NADH/NAD+ RATIO (5K08DK115881-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9986789. Licensed CC0.

---

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