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Targeting Uric Acid as a Therapeutic for NASH

Award Number: R01DK124510
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Targeting Uric Acid as a Therapeutic for NASH - 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 for diseases that display complex, multifactorial pathogenesis such as NASH.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $336,143 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/1/2023	NON-COMPETING CONTINUATION	$336,143
														Subtotal = $336,143

Issue Date FY: 2022 ( Subtotal = $336,854 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	1/29/2022	NON-COMPETING CONTINUATION	$303,168
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	3/25/2022	NON-COMPETING CONTINUATION	$33,686
														Subtotal = $336,854

Issue Date FY: 2021 ( Subtotal = $337,544 )
2021	2021	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	3/4/2021	NON-COMPETING CONTINUATION	$337,544
														Subtotal = $337,544

Issue Date FY: 2020 ( Subtotal = $350,505 )
2020	2020	UNIVERSITY OF PITTSBURGH THE	3520 FIFTH AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	4/29/2020	NEW	$350,505
														Subtotal = $350,505

Grand Total All Awards = $1,361,046

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Targeting Uric Acid as a Therapeutic for NASH

Award Number: R01DK124510

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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