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Sphingolipids in alcoholic liver disease

Award Number: R01AA030180
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: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Sphingolipids in alcoholic liver disease - Alcoholic liver disease (ALD) remains the most common chronic liver disease worldwide. Despite extensive studies, no FDA-approved therapy is available for any stage of ALD due to the limited understanding of disease pathogenesis. Therefore, the unmet need to identify novel targets for developing effective therapeutics against ALD is urgent. Alcohol not only alters hepatic lipid and bile acid metabolism but also disrupts the gut microbiome and intestinal barrier function, which results in a leaky gut and bacterial translocation as well as activation of systemic and hepatic inflammation. We have previously reported that conjugated bile acids activate sphingosine- 1 phosphate receptor 2 (S1PR2), which further activates ERK1/2 and AKT. S1P is one of the most studied sphingolipids and is synthesized from sphingosine by either sphingosine kinase 1 (SphK1) or SphK2. S1P can regulate various fundamental cellular responses either as an intracellular signaling molecule or a ligand for five GPCRs, S1PR1-5. SphK2-generated nuclear S1P is a potent natural inhibitor of histone deacetylases (HDAC1/2). Activation of the stimulator of interferon genes (STING) also has been identified as critical signaling in ALD. A recent study reported that SphK2-mediated production of nuclear S1P in CD11b+ macrophages is a strong inhibitor of STING and suppresses the inflammatory response in alveolar macrophages. We have reported that SphK2-/- mice developed more severe fatty liver and hepatic injury in the NIAAA ALD mouse model. Hepatic SphK2 expression levels were markedly reduced in both ALD cirrhotic patients and ALD mouse models. Alcohol-feeding significantly increased intestinal permeability and bacterial translocation in SphK2-/- mice. Our preliminary data further showed that 1) alcohol-feeding induced more severe liver injury in the global SphK2-/- mice than hepatocyte-specific SphK2 knockout (SphK2Hep-/-); 2) intestinal epithelial cell-specific SphK2 knockout (SphK2IEC-/-) mice were more prone to alcohol-induced liver injury compared to SphK2fl/fl mice; 3) RNAseq analysis showed that chronic alcohol feeding significantly disrupted hepatic sphingolipid, fatty acid, and bile acid metabolism and activated inflammatory and fibrotic responses; 4) deletion of SphK2 inhibited the growth of intestinal organoids. Based on these key findings, we HYPOTHESIZE that disruption of SphK2/S1P-mediated signaling pathways in the gut-liver axis plays a critical role in alcohol-induced liver injury. Two specific aims are proposed to test the hypothesis. 1) To investigate the role and mechanisms of SphK2 in modulating hepatic lipid metabolism and inflammatory response under the conditions of acute and chronic alcohol-induced stress. 2): To define the role of SphK2 in modulating intestinal barrier function and to identify the cellular mechanisms by which SphK2 modulates the gut liver axis in response to alcohol-induced stress. Accomplishing these specific aims will significantly advance our current understanding of the tissue and cell-type-specific roles of SphK2/S1P-mediated signaling pathways in ALD, which holds great promise for developing novel therapeutic interventions not only for ALD but also for other related metabolic 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: 2025 ( Subtotal = $523,062 )
2025	2025	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Alcohol Research Programs	000	3	5/15/2025	NON-COMPETING CONTINUATION	$523,062
														Subtotal = $523,062

Issue Date FY: 2024 ( Subtotal = $523,062 )
2024	2024	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Alcohol Research Programs	000	2	6/5/2024	NON-COMPETING CONTINUATION	$523,062
														Subtotal = $523,062

Issue Date FY: 2023 ( Subtotal = $523,062 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Alcohol Research Programs	000	1	6/22/2023	NEW	$523,062
														Subtotal = $523,062

Grand Total All Awards = $1,569,186

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Sphingolipids in alcoholic liver disease

Award Number: R01AA030180

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: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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