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Lipotoxicity in Alcoholic Liver Disease

Award Number: R01AA018844
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2009
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Lipotoxicity in Alcoholic Liver Disease - PROJECT SUMMARY / ABSTRACT Alcoholic liver disease (ALD) is a leading cause of morbidity and mortality in the United States and worldwide. Unfortunately, there is currently no FDA approved medication for any stage of ALD. Advancing our knowledge on the pathophysiologic mechanisms of ALD will certainly pave the way to development of therapeutic interventions. One of the known mechanisms of alcohol-induced liver injury is the perturbation of lipid metabolic pathways. In fact, alcoholic steatosis is the earliest pathological change in ALD. In the past funding period, we have shown that instead of triglyceride, accumulated free fatty acid (FFA) levels positively correct with disease severity in experimental models of ALD. However, how alcohol causes FFA accumulation in the liver and the feasibility of FFA lowering approaches for treating ALD are still open questions to be elucidated. Through profiling hepatic FFAs, we found that the most significantly altered and abundant FFA species were long chain FAs (LCFA) which were increased by alcohol. On the other hand, their activated forms, long chain acyl-CoAs, were decreased by alcohol, suggesting a defect in FA activation by long chain acyl-CoA synthetase (ACSL). Our preliminary study detected two ACSL isoforms in the liver, ACSL1 and ACSL4, that both were downregulated after alcohol exposure. ACSL1 is a major form of hepatic ACSLs that is critical for channeling FA to mitochondrial β-oxidation, whereas ACSL4 specifically targets arachidonic acid (AA) metabolism and has been reported to be critically involved in ER VLDL lipidation. Along with reduced VLDL secretion rate as well as its lipidation status, we indeed found that alcohol exposure decreases hepatic AA-CoA despite an increased AA. Moreover, we found that the expression of ACSL1 and ACSL4 were positively correlated with aryl hydrocarbon receptor both in vivo and in vitro. All evidence collected strongly supports a novel concept that defect in ACSL-mediated hepatic FA channeling plays a critical role in FA disposal disorder and in alcohol-induced lipotoxicity, which is tightly controlled by AhR. We will test the hypothesis in 3 aims. In Aim 1, we will investigate the role of ACSL1 in directing the metabolic switch toward mitochondrial β-oxidation versus ER ω-oxidation in order to reduce toxic lipid production from ER and to prevent lipotoxicity in ALD. In Aim 2, we will explore how ACSL4 is involved in AA channeling to ER for VLDL lipidation and/or to peroxisome for β-oxidation other than converting to toxic lipid mediators. In Aim 3, we will determine whether the expression of ACSL is regulated by AhR at transcription level. We also will test the effect of endogenous AhR ligand in reversing ACSL expression and protecting alcohol- induced lipotoxicity. Understanding these mechanisms will enable us to develop targeted dietary therapies to prevent and treat ALD.


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 = $411,145 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN ST	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	000	16	6/13/2024	NON-COMPETING CONTINUATION	$411,145
														Subtotal = $411,145

Issue Date FY: 2023 ( Subtotal = $411,145 )
2023	2023	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	000	15	7/4/2023	NON-COMPETING CONTINUATION	$411,145
														Subtotal = $411,145

Issue Date FY: 2022 ( Subtotal = $411,145 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	000	14	7/7/2022	NON-COMPETING CONTINUATION	$411,145
														Subtotal = $411,145

Issue Date FY: 2021 ( Subtotal = $411,145 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	002	13	7/7/2021	NON-COMPETING CONTINUATION	$411,145
2021	2020	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	001	12	2/9/2021	COMPETING CONTINUATION	$150,194
2021	2019	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	000	11	2/9/2021	NON-COMPETING CONTINUATION	-$150,194
														Subtotal = $411,145

Issue Date FY: 2020 ( Subtotal = $411,145 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	001	12	9/14/2020	COMPETING CONTINUATION	$411,145
2020	2019	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	000	11	9/14/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $411,145

Issue Date FY: 2019 ( Subtotal = $391,247 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	000	11	6/28/2019	NON-COMPETING CONTINUATION	$391,247
														Subtotal = $391,247

Issue Date FY: 2018 ( Subtotal = $391,247 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	000	10	6/19/2018	NON-COMPETING CONTINUATION	$391,247
														Subtotal = $391,247

Issue Date FY: 2017 ( Subtotal = $391,247 )
2017	2017	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	1000 SPRING GARDEN STREET	GREENSBORO	NC	27412	GUILFORD	USA	Alcohol Research Programs	000	9	6/21/2017	NON-COMPETING CONTINUATION	$391,247
														Subtotal = $391,247

Issue Date FY: 2016 ( Subtotal = $391,247 )
2016	2016	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	70 BOX, 26173	GREENSBORO	NC	27402	GUILFORD	USA	Alcohol Research Programs	000	8	6/3/2016	NON-COMPETING CONTINUATION	$391,247
														Subtotal = $391,247

Issue Date FY: 2015 ( Subtotal = $388,951 )
2015	2015	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	70 BOX, 26173	GREENSBORO	NC	27402	GUILFORD	USA	Alcohol Research Programs	000	7	8/19/2015	COMPETING CONTINUATION	$388,951
														Subtotal = $388,951

Issue Date FY: 2013 ( Subtotal = $262,340 )
2013	2013	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	70 BOX, 26173	GREENSBORO	NC	27402	GUILFORD	USA	Alcohol Research Programs	000	6	8/7/2013	NON-COMPETING CONTINUATION	$262,340
														Subtotal = $262,340

Issue Date FY: 2012 ( Subtotal = $282,086 )
2012	2012	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	70 BOX, 26173	GREENSBORO	NC	27402	GUILFORD	USA	Alcohol Research Programs	000	5	7/24/2012	NON-COMPETING CONTINUATION	$282,086
														Subtotal = $282,086

Issue Date FY: 2011 ( Subtotal = $282,085 )
2011	2011	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	70 BOX, 26173	GREENSBORO	NC	27402	GUILFORD	USA	Alcohol Research Programs	002	4	8/9/2011	NON-COMPETING CONTINUATION	$282,086
2011	2010	UNIVERSITY OF NORTH CAROLINA AT GREENSBORO	70 BOX, 26173	GREENSBORO	NC	27402	GUILFORD	USA	Alcohol Research Programs	000	3	12/10/2010	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$311,354
2011	2010	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Alcohol Research Programs	001	2	12/10/2010	NON-COMPETING CONTINUATION	-$311,355
														Subtotal = $282,085

Issue Date FY: 2010 ( Subtotal = $311,355 )
2010	2010	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Alcohol Research Programs	000	2	8/26/2010	NON-COMPETING CONTINUATION	$311,355
														Subtotal = $311,355

Issue Date FY: 2009 ( Subtotal = $314,500 )
2009	2009	UNIVERSITY OF LOUISVILLE RESEARCH FOUNDATION	SERVICE COMPLEX	LOUISVILLE	KY	40292	JEFFERSON	USA	Alcohol Research Programs	000	1	9/22/2009	NEW	$314,500
														Subtotal = $314,500

Grand Total All Awards = $5,462,030

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Lipotoxicity in Alcoholic Liver Disease

Award Number: R01AA018844

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2009

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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