# Targeting Uric Acid as a Therapeutic for NASH

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $336,854

## Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. The most common risk
factors associated with NAFLD are obesity, type 2 diabetes and dyslipidemia, with 80-90% of obese adults
developing NAFLD. Simple steatosis is generally inert pathologically but in the presence of inflammation,
defined as non-alcoholic steatohepatitis (NASH), is a gateway to more severe forms of liver disease including
cirrhosis and liver failure. As waistlines continue to expand, NAFLD is now considered the next global
epidemic, as it is associated with increased risk of metabolic syndrome, cardiovascular disease and cancer.
Two of the largest untargeted metabolome studies revealed uric acid (UA) as the most significant metabolite
associated with obesity and is a better predictor than the next six metabolites combined. UA is generated
solely from xanthine oxidase (XO) during the catabolism of purines. Recent publications and preliminary data
herein reveal that XO activity is increased in conjunction with UA in obesity and in clinical and experimental
NAFLD. During this catabolism of purines by XO, toxic reactive oxygen species (ROS) are generated that can
damage biomolecules and contribute to injury. Indeed, the current dogma is that ROS generated from XO are
directly responsible for this enzyme’s injurious role in inflammation and injury. However, this dogma ignores
the fact that UA also is a toxic species that induces inflammation, mitochondrial dysfunction and ROS
generation in other diseases. Whether or not UA plays a similar deleterious role in NAFLD remains unclear.
Elucidating whether ROS or UA is the predominant XO-derived toxic metabolite in NAFLD pathogenesis fills
critical gaps in knowledge and reveals new therapeutic options.
A longitudinal mouse study revealed that a fast food diet (FFD) consisting of high- fat, -fructose and -
cholesterol recapitulates the NASH phenotype observed clinically. It is believed that fructose metabolism
activates the purine catabolism pathway (via XO) resulting in the culmination of UA although the exact
mechanism is unclear. Therefore, we will test the hypothesis this fast food diet leads to hyperuricemia and
promotes the progression of NAFLD to NASH. To test this hypothesis, these aims will be tested: (1)-
Determine whether hyperuricemia is causally responsible for mitochondrial stress, insulin resistance and
hepatic steatosis in experimental NAFLD/NASH; and (2)-Determine whether pharmacologically targeting XO is
sufficient enough to slow the progression from NAFLD to NASH. Understanding the pathophysiology of
hyperuricemia and whether it directly causes mitochondrial dysfunction resulting in the progression of
NAFLD to NASH will fill critical knowledge gaps. Additionally, successful outcomes will determine if
inhibiting XO (novel target) with febuxostat is sufficient enough to protect against NAFLD/NASH or a
one drug-multiple target approach using nitro-oleic acid will provide better responses f...

## Key facts

- **NIH application ID:** 10364671
- **Project number:** 5R01DK124510-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Eric Eugene Kelley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $336,854
- **Award type:** 5
- **Project period:** 2020-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10364671

## Citation

> US National Institutes of Health, RePORTER application 10364671, Targeting Uric Acid as a Therapeutic for NASH (5R01DK124510-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10364671. Licensed CC0.

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