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Impaired phospholipid methylation results in decreased lipid droplet lipolysis: Role in hepatic steatosis

Award Number: R01AA026723
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT The development of fatty liver (steatosis) is an early manifestation of alcoholic liver disease (ALD) that can progress to alcoholic hepatitis and cirrhosis with continued alcohol misuse. Hepatic steatosis is a reversible early stage of ALD and is, therefore, a prime target for therapeutic intervention. Our long term objectives are to (i) understand the mechanisms of alcoholic steatosis development and (ii) formulate strategies for treatment/prevention of this and other fatty liver diseases with similar histopathology and progression history. We have previously shown that reduction in phosphatidylethanolamine methyltransferase (PEMT) impairs very-low-density lipoproteins (VLDL) secretion contributing to alcoholic steatosis. PEMT catalyzes the methylation of phosphatidylethanolamine (PE) to generate phosphatidylcholine (PC), which is necessary for normal VLDL assembly and secretion. We have further shown that treatment with betaine, a methyl donor, normalizes PEMT-catalyzed PC synthesis to promote VLDL secretion and prevent alcoholic steatosis. It has been demonstrated that hepatic cytoplasmic lipid droplets (LDs) play an integral role in VLDL biogenesis. This is because VLDL assembly is regulated by the availability of triglycerides stored in these LDs which have to be hydrolyzed to provide substrates for VLDL assembly. LDs are surrounded by a monolayer of phospholipids; PC is the most abundant class followed by PE and others. Further, an orbit of proteins determines the metabolic fate of LD lipid stores. Based on these considerations, we present a novel hypothesis that impaired phospholipid methylation contributes to the development of hepatic steatosis by impairing LD lipolysis. We propose that the ethanol- induced impairment in PEMT-catalyzed PC decreases the PC:PE ratio in the LD monolayer. This promotes generation of enlarged LDs with significant alterations in the complement of LD-associated proteins. These changes together affect the lipolysis of the LD triglyceride stores disrupting the assembly and secretion of VLDL resulting in liver steatosis. We further hypothesize that dietary betaine supplementation reverses alcoholic steatosis by normalizing LD PC:PE ratio and VLDL biogenesis. To test our hypothesis, we propose the following Specific Aims: Specific Aim 1: To characterize how ethanol alters the phospholipid and protein composition of hepatic LDs. Specific Aim 2: To examine the effect of alcohol on LD lipolysis for mobilization of triglyceride stores for VLDL secretion. Specific Aim 3: To determine the effects of betaine on alcohol-induced alterations in LD dynamics. Completion of these studies will provide insight into the importance of maintaining the essential methylation reaction catalyzed by PEMT in regulating the dynamics of lipid droplet and preventing the development of alcoholic steatosis and other chronic liver diseases including non-alcoholic 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: 2024 ( Subtotal = $0 )
2024	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	5	3/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $314,573 )
2022	2022	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	5	3/30/2022	NON-COMPETING CONTINUATION	$314,573
														Subtotal = $314,573

Issue Date FY: 2021 ( Subtotal = $314,573 )
2021	2021	BOARD OF REGENTS OF THE UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	4	4/23/2021	NON-COMPETING CONTINUATION	$314,573
														Subtotal = $314,573

Issue Date FY: 2020 ( Subtotal = $314,573 )
2020	2020	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	3	4/7/2020	NON-COMPETING CONTINUATION	$314,573
														Subtotal = $314,573

Issue Date FY: 2019 ( Subtotal = $314,573 )
2019	2019	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	2	3/26/2019	NON-COMPETING CONTINUATION	$314,573
														Subtotal = $314,573

Issue Date FY: 2018 ( Subtotal = $314,573 )
2018	2018	UNIVERSITY OF NEBRASKA	987835 NEBRASKA MEDICAL CENTER	OMAHA	NE	68198	DOUGLAS	USA	Alcohol Research Programs	000	1	5/2/2018	NEW	$314,573
														Subtotal = $314,573

Grand Total All Awards = $1,572,865

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Impaired phospholipid methylation results in decreased lipid droplet lipolysis: Role in hepatic steatosis

Award Number: R01AA026723

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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