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Molecular and cellular analysis of the ABHD5/PNPLA3 metabolon in lipid homeostasis

Award Number: R01DK126743
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: 07/19/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Molecular and cellular analysis of the ABHD5/PNPLA3 metabolon in lipid homeostasis - Project Summary/Abstract The balance between triacylglycerol (TAG) storage and mobilization in adipose tissue and liver is critical to metabolic health as the dysregulation during obesity can produce ectopic accumulation of lipids in muscle and liver, resulting in the progression to diabetes and fatty liver disease (FLD). Thus, an important long-term scientific goal is to understand the tissue-specific molecular mechanisms that control TAG metabolism in order to discover novel therapies. Patatin-Like Phospholipase Domain Containing 3 (PNPLA3) is a protein that is highly expressed in lipogenic tissues, like fat and liver, and is highly upregulated under conditions that promote fat storage. Importantly, a common genetic variant of PNPLA3, I148M, is the greatest known risk factor for developing FLD and its pathological sequelae. In recently published and preliminary data, we demonstrate that α/β hydrolase domain containing protein 5 (ABHD5), an enzyme co-activator, strongly interacts with PNPLA3 and the disease-causing I148M variant is a gain-of-function. Furthermore, the interaction between PNPLA3 I148M and ABHD5 is particularly effective in promoting cellular TAG retention, which likely plays a central role in disease progression. Importantly, the ABHD5/PNPLA3 interaction can be dynamically regulated by endogenous fatty acids and synthetic ABHD5 ligands. This work will examine the basic mechanism of how ABHD5 regulates the function of PNPLA3 and the I148M variant in adipocytes and hepatocytes using high resolution imaging techniques, proximity proteomics and metabolic tracers/lipidomics in conjunction with robust genetic models and an integrative panel of endogenous fatty acid ligands and chemical probes. Our Specific Aims are: 1) To determine the molecular basis for the interaction of ABHD5 with WT PNPLA3 and I148M and the subcellular location and dynamic trafficking of ABHD5 complexes in adipocytes and hepatocytes using high resolution fluorescence and transmission electron microscopy. 2) To determine the location and ligand-dependent protein composition of the ABHD5/PNPLA3 and ABHD5/ PNPLA3 I148M metabolons using nonbiased proximity proteomics and directed immunoprecipitation. 3) To dissect the metabolic function of the ABHD5/PNPLA3 and ABHD5/PNPLA3 I148M metabolons in adipocytes and hepatocytes using gain- and loss- of-function genetics and selective endogenous and synthetic ABHD5 ligands in conjunction with isotope tracers and lipidomics. These goals, which are well aligned with the mission of the NIH will be implemented within a discovery platform that maximizes integration across level of analysis (molecular, organelle, cells and tissues) to provide a robust analysis of ABHD5/PNPLA3 function, thereby improving our understanding of how lipids levels are regulated and identify novel points for therapeutic intervention in obesity related disorders.


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 = $476,166 )
2025	2025	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	6/23/2025	NON-COMPETING CONTINUATION	$476,166
														Subtotal = $476,166

Issue Date FY: 2024 ( Subtotal = $457,120 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/17/2024	NON-COMPETING CONTINUATION	$457,120
														Subtotal = $457,120

Issue Date FY: 2023 ( Subtotal = $476,166 )
2023	2023	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/26/2023	NON-COMPETING CONTINUATION	$476,166
														Subtotal = $476,166

Issue Date FY: 2022 ( Subtotal = $476,166 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/29/2022	NON-COMPETING CONTINUATION	$476,166
														Subtotal = $476,166

Issue Date FY: 2021 ( Subtotal = $472,506 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/19/2021	NEW	$472,506
														Subtotal = $472,506

Grand Total All Awards = $2,358,124

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Molecular and cellular analysis of the ABHD5/PNPLA3 metabolon in lipid homeostasis

Award Number: R01DK126743

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: 07/19/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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