# The role of neutral ceramidase in intestinal fucosylation and liver steatosis and inflammation

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2022 · $413,160

## Abstract

There is an increasing evidence that demonstrates a critical pathogenic role for the “gut-liver axis” in the
development of nonalcoholic fatty liver diseases (NAFLD). Gut-derived endotoxin leakiness is increased under
pathological conditions, including high fat diet (HFD) consumption. Gut fucosylation is a key force in maintaining
a homeostatic relationship between the gut and its microbiota. Nevertheless, it is unclear how host fucosylation
machinery contributes to obesity-associated intestinal barrier function, microbial translocation and inflammation.
Glycosphingolipids (GSLs) are major constituents of enterocytes and consist of glycans conjugated to a lipid
(ceramide) core. Ceramide is at the center of sphingolipid metabolism, and is hydrolyzed to generate sphingosine
and fatty acid by ceramidases including neutral ceramidase (NcDase). However, whether gut NcDase
contributes to intestinal fucosylation in NAFLD is unclear. We found that deletion of intestinal epithelial cells
(IECs) NcDase induced marked upregulation of intestinal fucosylation in response to HFD exposure. Our
preliminary studies further demonstrated that HFD-fed NcDase-/- mice have increases in intestinal AhR activity,
IL-22 secretion and the production of fucosylated gangliosides (fucosyl-GM1). We also found that fucosyl-GM1
can bind to DC-SIGN, a C-type lectin, expressed in hepatic macrophages and can induce anti-inflammatory M2
macrophage. This has led to the central hypothesis that gut NcDase regulates the intestinal fucosylation
and subsequent barrier function via IEC AhR signal; and that IECs NcDase-derived fucosylated
glycosphingolipids induce hepatic macrophage polarization via fucosyl-GM1/DC-SIGN pathway and
prevent the development of NAFLD. Importantly, the proposal also pursues translational studies that examine
the efficacy of prebiotic 2′-FL feeding and fucosyl-GM1 treatment targeted at intestinal fucosylation and hepatic
inflammatory macrophages in mitigating gut-liver axis changes. Following specific aims will be carried out: Aim
1: Determine the impact of NcDase on the gut fucosylation and the effects of this impact on intestinal barrier
integrity. We will determine the impact of NcDase-related gut microbiota on the gut fucosylaton and barrier
function. Aim 2: Determine whether NcDase regulation of IEC AhR contributes to gut fucosylation via microbial
metabolite in response to HFD exposure. Aim3: Determine whether IEC NcDase-derived fucosylated
gangliosides contribute to the induction of liver tolerogenic macrophages and evaluate the efficacy of
fucosylation-based therapeutic interventions in NAFLD. Our studies on the NcDase-mediated gut fucosylation
and prebiotic intervention will likely bring new mechanistic understanding and identify new therapeutic targets
for the prevention and treatment of NAFLD.

## Key facts

- **NIH application ID:** 10517197
- **Project number:** 1R01DK131442-01A1
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Zhong-Bin Deng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $413,160
- **Award type:** 1
- **Project period:** 2022-06-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10517197

## Citation

> US National Institutes of Health, RePORTER application 10517197, The role of neutral ceramidase in intestinal fucosylation and liver steatosis and inflammation (1R01DK131442-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10517197. Licensed CC0.

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