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Hepatic SLC25a25 in Steatotic Liver Disease Progression

Award Number: F31DK139728
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 07/31/2027

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Hepatic SLC25a25 in Steatotic Liver Disease Progression - ABSTRACT The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is rapidly increasing and impacts 25% of the global population. Metabolic dysfunction-associated steatohepatitis (MASH) is the fastest growing cause of cirrhosis and liver cancers, but there are no approved targeted therapies for MASH to date. Thus, there is a critical need to investigate the mechanistic regulators of MASH to develop effective treatments. Mitochondria are the primary organelles involved in hepatic substrate oxidation and energy production. Declines in hepatic mitochondrial respiratory capacity occur in parallel with MASH progression, making mitochondrial regulators potential treatments for MASH. Nuclear-encoded mitochondrial protein SLC25a25 transports ATP and inorganic phosphate, thus regulating metabolic potential. SLC25a25 is a critical regulator of ATP availability, which directly impacts rates of mitochondrial oxidation through alteration of the adenylate pool. The goal of this proposal is to examine the role and regulation of SLC25a25 in the onset and progression of MASH. The overarching hypothesis is that SLC25a25 is activated in MASLD to restrict hepatic lipid deposition and progression to MASH via increased mitochondrial fatty acid oxidation. In Aim 1, I will perform the first cross- sectional analysis of SLC25a25 expression in human samples from patients with obesity across the MASLD spectrum. In Aim 2, I will employ a hepatocyte-specific loss-of-function model in mice to mechanistically dissect the role of SLC25a25 in the onset and progression of MASH. This project will reveal the role of SLC25a25 on MASH development through regulations of hepatic mitochondrial function and metabolic potential. Determination of the mechanism of SLC25a25 on hepatic mitochondrial function will provide further understanding of the role of mitochondrial transporters on metabolic function and disease development, paving the way for the development of new treatments for MASH. The experimental approach harnesses innovative transgenic and molecular approaches supported by physiologically relevant first-in-human evidence of SLC25a25 expression to obtain meaningful data on MASH progression. The findings of this proposal have the potential to provide the conceptual framework for the development of targeted pharmacotherapies for MASH, which can impact clinical care and outcomes for patients with liver disease.


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: 2025 ( Subtotal = $43,031 )
2025	2025	PENNINGTON BIOMEDICAL RESEARCH CENTER	6400 PERKINS RD	BATON ROUGE	LA	70808	EAST BATON ROUGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/4/2025	NON-COMPETING CONTINUATION	$43,031
														Subtotal = $43,031

Issue Date FY: 2024 ( Subtotal = $42,467 )
2024	2024	LSU PENNINGTON	6400 PERKINS RD	BATON ROUGE	LA	70808	EAST BATON ROUGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/7/2024	NEW	$41,187
2024	2024	LSU PENNINGTON	6400 PERKINS RD	BATON ROUGE	LA	70808	EAST BATON ROUGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	1	5/3/2024	NEW	$0
2024	2024	LSU PENNINGTON	6400 PERKINS RD	BATON ROUGE	LA	70808	EAST BATON ROUGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	5/3/2024	NEW	$1,280
														Subtotal = $42,467

Grand Total All Awards = $85,498

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Hepatic SLC25a25 in Steatotic Liver Disease Progression

Award Number: F31DK139728

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 07/31/2027

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