# Sphingosine-1 phosphate signaling in alcoholic liver disease

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $184,359

## Abstract

Alcoholic liver disease (ALD) remains the most common chronic liver diseases worldwide. During last several
decades, extensive studies have shown that ALD progression involves multiple events such as hepatic lipid
accumulation, intestinal barrier dysfunction, and activation of an inflammatory response. Currently, no FDA
approved therapy is available for any stage of ALD. Therefore, the unmet need to identify novel targets for the
development of effective therapeutics against ALD is urgent. It has been shown that alcohol alters bile acid
metabolism and disrupts intestinal barrier function, which results in leaky gut and bacterial translocation and
activation of systemic and hepatic inflammation. Bile acids are important signaling molecules involved in
regulating lipid metabolism. Our lab first discovered a link between conjugated bile acids and sphingosine-1
phosphate (S1P) signaling in regulating hepatic lipid and glucose metabolism. The conjugated bile acids activate
S1P receptor 2 (S1PR2), which further activate sphingosine kinase 2 (SphK2). S1P is a membrane-derived lipid
mediator, which is synthesized from sphingosine by either SphK1 or SphK2. It has been identified that S1P can
regulate various fundamental cellular responses either as an intracellular signaling molecule or a ligand for five
cell membrane G-protein coupled receptors (GPCRs), S1PR1-5. SphK1 is primarily located in the cytoplasm of
mammalian cells, whereas SphK2 is located in the nucleus and mitochondria. SphK2-generated nuclear S1P is
a powerful natural inhibitor of histone deacetylases (HDAC1/2). Increased histone acetylation is often associated
with an increase in the transcriptional activity of genes involved in cell proliferation, migration and angiogenesis.
We recent reported that both S1PR2 and SphK2 knock out mice (S1PR2-/- and SphK2-/-) are highly susceptible
to high fat diet-induced fatty liver and hepatic lipotoxicity. Activation of SphK2 in response to ER stress
ameliorates hepatic steatosis. The preliminary results further showed that SphK2-/-mice developed more severe
fatty liver and hepatic injury as indicated by increased hepatic lipid accumulation and inflammation after 10-day’s
feeding with 5% ethanol liquid diet (Lieber-DeCarli) followed by a binge via 31.5% ethanol gavage or two-month
chronic feeding with 5% alcohol liquid diet. In addition, alcohol-feeding significantly increased intestinal
permeability and bacterial translocation in SphK2-/- mice. Furthermore, both LPS and thapsigargin (an ER stress
inducer) inhibited intestinal organoid growth. Based on these key findings, we HYPOTHESIZE that disruption of
SphK2/S1P-mediated signaling pathways plays a critical role in alcohol-induced liver injury. Two specific aims
are proposed to test our central hypothesis:1) To investigate the role of SphK2 in alcohol induced-liver injury. 2)
To identify the potential mechanisms by which lack of SphK2 promotes hepatic injury in response to chronic
alcohol consumption. ...

## Key facts

- **NIH application ID:** 9929515
- **Project number:** 5R21AA026629-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** HUIPING ZHOU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $184,359
- **Award type:** 5
- **Project period:** 2019-05-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929515

## Citation

> US National Institutes of Health, RePORTER application 9929515, Sphingosine-1 phosphate signaling in alcoholic liver disease (5R21AA026629-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9929515. Licensed CC0.

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