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Regulation of Endothelial Lipase and HDL Metabolism by ANGPTL3

Award Number: R01HL162698
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/13/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Regulation of Endothelial Lipase and HDL Metabolism by ANGPTL3 - PROJECT SUMMARY Despite currently available treatments, cardiovascular disease remains the leading cause of death in the United States. As dysregulated lipoprotein metabolism contribute to cardiovascular disease, there is a critical need to decipher the lipoprotein pathways, including those regulated by ANGPTL proteins, that drive cardiovascular pathologies. The long-term goal of the proposed research is to understand how ANGPTL proteins regulate lipid homeostasis and how these proteins become dysregulated in disease. One ANGPTL protein, the hepatokine ANGPTL3, inhibits both endothelial lipase (EL) and lipoprotein lipase, and thus regulates both plasma cholesterol and triglycerides. The objective in this application is to identify the mechanisms by which ANGPTL3 regulates EL and how this regulation affects HDL metabolism and cardiovascular disease. The central hypothesis of this study is that ANGPTL3 inhibits EL by promoting structural changes that disrupt its stability, and that this inhibition prevents the pathologic remodeling of HDL that contributes to atherosclerosis. This hypothesis will be tested by pursuing two specific aims: 1) Determine the effects of ANGPTL3-mediated EL inhibition on atherosclerosis and HDL function; and 2) Identify the mechanism by which ANGPTL3 inhibits EL. The studies in aim 1 use mice that express mutant ANGPTL3 alleles that only inhibit EL or LPL. These mice will be crossed with ApoE knockout mice to determine the respective contributions of ANGPTL3-mediated EL inhibition and LPL inhibition to atherosclerosis. These mice will also be used to determine the physiologic locations of EL inhibition using tissue phospholipase activity assays. Radioactive tracer experiments will be used to determine how inhibition of EL by ANGPTL3 alters HDL-lipid partitioning, and a variety of HDL functional assays will be used to determine how this inhibition alters the anti-atherogenic functions of HDL. In aim 2, various biochemical analyses, including phospholipase activity assays, site-directed mutagenesis, and hydrogen-deuterium exchange mass spectrometry, will be used to probe the functional interactions of ANGPTL3 with EL. The proposed studies are innovative in their use of ANGPTL3 alleles that only inhibit LPL or only inhibit EL to decouple the physiological effects of LPL and EL inhibition. The proposed studies are significant because lipoprotein homeostasis is essential for cardiovascular health. Therefore, uncovering how and where ANGPTL3 inhibits EL activity, and how this inhibition impacts HDL function, HDL metabolism, and the progression of atherosclerosis will increase our fundamental understanding of how lipoprotein metabolism is regulated. Completion of the aims outlined in this study will have a broad positive impact as lipoprotein metabolism contributes to many metabolic diseases, and thus understanding how the regulators of these pathways, including ANGPTL3, can best be therapeutically targeted may have wide-reaching implications for improved outcomes for these diseases.


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 = $501,095 )
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	4	1/31/2026	NON-COMPETING CONTINUATION	$485,756
2026	2026	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	001	4	3/13/2026	NON-COMPETING CONTINUATION	$15,339
														Subtotal = $501,095

Issue Date FY: 2025 ( Subtotal = $469,522 )
2025	2025	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	3	12/13/2024	NON-COMPETING CONTINUATION	$469,522
														Subtotal = $469,522

Issue Date FY: 2024 ( Subtotal = $515,746 )
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	001	2	6/14/2024	NON-COMPETING CONTINUATION	$42,100
2024	2024	THE UNIVERSITY OF IOWA	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	2	12/13/2023	NON-COMPETING CONTINUATION	$473,646
														Subtotal = $515,746

Issue Date FY: 2023 ( Subtotal = $540,148 )
2023	2023	UNIVERSITY OF IOWA, THE	105 JESSUP HALL	IOWA CITY	IA	52242	JOHNSON	USA	Cardiovascular Diseases Research	000	1	1/13/2023	NEW	$540,148
														Subtotal = $540,148

Grand Total All Awards = $2,026,511

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Regulation of Endothelial Lipase and HDL Metabolism by ANGPTL3

Award Number: R01HL162698

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/13/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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