# Role of SMPDL3B in obesity-associated  non-alcoholic fatty liver disease

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $459,040

## Abstract

Obesity is an independent risk factor for development of non-alcoholic fatty liver disease (NAFLD). With the
epidemic burden of obesity and metabolic diseases, NAFLD occurrence is steadily rising, along with the need
for therapeutic options of this disease. Preliminary data from rodent and human studies provide strong
evidence to support the hypothesis that monocyte/macrophage-derived TSP1 in obesity downregulates liver
macrophage SMPDL3B and this downregulation feeds back to increase TSP1 binding to its receptor-CD36.
This positive feedback loop together with SMPDL3B’s action on TLR pathways further amplifies liver
macrophage pro-inflammatory signaling and leads to NAFLD progression. In this proposal, how SMPDL3B
regulates CD36 function and then TSP1-CD36 dependent pro-inflammatory signaling in macrophages will be
determined in Aim 1. The in vivo importance of macrophage SMPDL3B in NAFLD development and
progression in both animal models and human liver organoids will be determined in Aim 2. Whether specific
blockade of TSP1/CD36 interaction upregulates liver macrophage SMPDL3B and attenuates liver pro-
inflammatory signaling and NAFLD development and progression will be determined in Aim 3. Completing
these studies will provide novel information on the mechanisms by which suppressed macrophage SMPDL3B
enhances liver macrophage pro-inflammatory signaling and its critical role in the progression of obesity-
associated NAFLD to NASH. Further, testing a novel therapeutic application of a peptide nanoparticle
conjugate to block TSP1/CD36 interaction in obesity-associated NASH in vivo will have translational
significance.

## Key facts

- **NIH application ID:** 10832079
- **Project number:** 5R01DK131786-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Shuxia Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $459,040
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832079

## Citation

> US National Institutes of Health, RePORTER application 10832079, Role of SMPDL3B in obesity-associated  non-alcoholic fatty liver disease (5R01DK131786-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10832079. Licensed CC0.

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