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Bilirubin Catabolism induces Plasminogen-Activator Inhibitor 1 (PAI-1) worsening Metabolic Dysfunction

Award Number: F31HL170972
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Bilirubin Catabolism induces Plasminogen-Activator Inhibitor 1 (PAI-1) worsening Metabolic Dysfunction - Summary: Urobilin is formed in the intestine as a biproduct of conjugated bilirubin catabolism. Currently, the physiological function of urobilin is unknown. Human association studies have indicated a positive correlation to obesity and cardiovascular diseases (CVD). Since obesity is a major risk factor for the development of CVD, we hypothesized that urobilin levels might change with the altered metabolic state and induce adiposity. To determine the role of urobilin in lean mice, we treated C57/bl6 mice on a normal-chow diet with urobilin for 4 weeks. We found that urobilin had no effect on body weight but significantly increased adiposity in the inguinal white adipose tissue (iWAT) depot compared to the vehicle-treated mice. To determine how urobilin changes the transcriptome profile in the iWAT, we preformed RNA-sequencing which showed that urobilin increases the expression of Serpine1 mRNA. Serpine1 is translated into the protein plasminogen activator inhibitor-1 (PAI-1). PAI-1 is secreted into circulation, promoting a prothrombotic environment, and is thought to increase the risk of CVD. The goal of this research proposal is to determine whether urobilin induces CVD via PAI-1 and if this mechanism is a link between CVD and obesity. We will investigate if lowering plasma urobilin is a possible therapeutic for the treatment and prevention of CVD. To study this, in Aim 1, we will use PAI-1 knockout (KO) mice and littermate controls treated with urobilin or vehicle while on a high-fat or calorie-match low-fat diets. We expect the PAI-1KO mice will be protected from urobilin induced CVD. In Aim 2, we will use diet-induced obese (DIO) mice treated with a liver- specific GalNac-Ugt1a1-RNAi or GalNac-scramble control to suppress hepatic Ugt1a1, which is responsible for initiating the conjugation of bilirubin that leads to elevated urobilin production. We show preliminary data that the RNAi technology suppresses Ugt1a1 94.7% and that this leads to a significant (p<0.01) decrease in plasma urobilin and an increase in plasma unconjugated bilirubin. We expect that the suppression of Ugt1a1 will protect the mice from the development of CVD by lowering urobilin levels, increasing unconjugated bilirubin, preventing adiposity and high PAI-1 plasma levels. This is the first proposed mechanism of urobilin in promoting the development of CVD, which we will extensively study to better understand how to reverse its deleterious effects. This fellowship will provided critical training in research techniques, scientific training and professional development to give me the tools to become a successful independent scientist.


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: 2026 ( Subtotal = $35,530 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	3	2/25/2026	NON-COMPETING CONTINUATION	$35,530
														Subtotal = $35,530

Issue Date FY: 2025 ( Subtotal = $35,530 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	001	2	9/6/2025	NON-COMPETING CONTINUATION	$564
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	2	12/5/2024	NON-COMPETING CONTINUATION	$34,966
														Subtotal = $35,530

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	1	1/8/2024	NEW	$0
2024	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	001	1	1/8/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $33,686 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Cardiovascular Diseases Research	000	1	8/18/2023	NEW	$33,686
														Subtotal = $33,686

Grand Total All Awards = $104,746

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Bilirubin Catabolism induces Plasminogen-Activator Inhibitor 1 (PAI-1) worsening Metabolic Dysfunction

Award Number: F31HL170972

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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