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The Role of ERRa in liver lipid dysfunction and pathology

Award Number: R01DK131492
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: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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The Role of ERRa in liver lipid dysfunction and pathology - Estrogen-related receptor (ERR) plays critical roles in the transcriptional regulation of genes involved in mitochondrial bioenergetics, TCA cycle, mitochondrial oxidative phosphorylation, and fatty acid -oxidation. This project intends to discover the roles of ERR as novel transcriptional factor for lipid metabolism and its involvement in pathology development in the liver. To address the function of ERR in dyslipidemia, we developed a novel small molecule inhibitor (ERR-PA) that can block the binding of ERRs to the promoters of their target genes. Using this compound in diet and genetic models of liver steatosis (NAFLD/ALD) and steatohepatitis (NASH/ASH), our preliminary studies showed that inhibiting ERR robustly blocks the development of steatosis and reverses the lipid accumulation in models where liver steatosis is induced by diet and ethanol feeding as well as genetic alterations. ERR-PA also significantly reduced the fibrosis and inflammation occurring in established steatohepatitis. Using these in vivo as well as in vitro systems, we will explore the molecular mechanisms by which ERR inhibition suppresses the progression of liver disease. The hypothesis to be tested is that ERRs positively regulate transcription of genes encoding enzymes for anabolic lipid metabolism and inhibiting this action blocks steatosis and associated inflammation and fibrosis in NASH/ASH. We will address this hypothesis with the following three aims. Aim1 will investigate the regulation of liver lipid metabolism via the transcriptional activity of ERRs. This aim will explore the transcriptional complex by which ERR regulates de novo lipogenesis, glycerolipid biosynthesis and fatty acid -oxidation. Aim2 will determine the effect of ERR inhibition on oxidative lipid damage during ASH/NASH development. This aim will investigate lipid, oxidized lipid and other derivatives, ROS production and their contribution to liver damage. The proposed project explores ERR as a potential target for inhibiting and reversing fatty liver diseases. The mechanistic and translational approaches will uncover novel biology for lipid metabolism as well as test the therapeutic effect of a small molecule polyamide.


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 = $363,000 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	6/18/2025	NON-COMPETING CONTINUATION	$36,300
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/9/2024	NON-COMPETING CONTINUATION	$326,700
2025	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	4/29/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $363,000

Issue Date FY: 2024 ( Subtotal = $400,321 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	11/10/2023	SUPPLEMENT FOR EXPANSION	$46,657
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/9/2023	NON-COMPETING CONTINUATION	$326,700
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	5/10/2024	SUPPLEMENT FOR EXPANSION	$5,184
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	5/9/2024	NON-COMPETING CONTINUATION	$21,780
														Subtotal = $400,321

Issue Date FY: 2023 ( Subtotal = $388,878 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	1/5/2023	NON-COMPETING CONTINUATION	$36,300
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/7/2022	NON-COMPETING CONTINUATION	$326,700
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	5/18/2023	SUPPLEMENT FOR EXPANSION	$25,878
														Subtotal = $388,878

Issue Date FY: 2022 ( Subtotal = $363,000 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/24/2021	NEW	$363,000
														Subtotal = $363,000

Grand Total All Awards = $1,515,199

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The Role of ERRa in liver lipid dysfunction and pathology

Award Number: R01DK131492

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: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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