# Analysis of Lipolytic Trafficking in Adipocytes.

> **NIH NIH R01** · WAYNE STATE UNIVERSITY · 2022 · $463,992

## Abstract

Project Summary/Abstract
 Disruption of cellular neutral lipid metabolism promotes the progression of obesity, diabetes, fatty liver
disease, and cancer. The long-term scientific goal of the project is to understand the molecular mechanisms
that control lipid storage and mobilization in order to identify novel points for therapeutic intervention.
 ABHD5 regulates cellular lipid metabolism, including PNPLA2/ATGL, the rate-limiting triglyceride lipase
in key metabolic tissues. Nonetheless, the mechanisms by which ABHD5, a protein lacking enzymatic activity,
activates PNPLA2 (and other PNPLAs) remains an important mystery.
 We hypothesize that the remodeling of biological membranes is a general mechanism by which ABHD5
regulates enzyme access to membrane-delimited neutral lipid substrates. Mechanistically, we hypothesize that
ligand binding stabilizes ABHD5 molecular and macromolecular conformations that target and alter membrane
biophysical properties (tension and curvature) to allow the lipase access to specific substrates sequestered
within lipid droplets (LDs). We will test this hypothesis using novel chemical probes of ABHD5 and informative
genetic mutants in live adipocytes (Aim 1). We will directly assess the impact ABHD5 on the biophysical
properties of membranes in model LD systems using an array of high resolution and high throughput
approaches (Aim 2). These Aims are designed to be highly complementary and to provide strong cross-
validation between experimental platforms.
 In addition, we present data demonstrating that ABHD5 is targeted to specific subcellular sites where
LDs form upon fatty acid supplementation. Furthermore, the interaction of ABHD5 with PLIN5, driven by the
ABHD5 ligand oleoyl-CoA, facilitates LD formation. Aim 3 will dissect the biochemical pathways promoted by
ABHD5/PLIN5 complexes and, in concert with Aim 2, evaluate the impact of this interaction on the biophysical
properties of model membranes.
 ABHD5 is emerging as a compelling therapeutic target for metabolic diseases and cancer. The results
of this project will provide new insights into specific mechanisms by which ABHD5 regulates fatty acid flux at
the cytosol/LD interface.

## Key facts

- **NIH application ID:** 10376253
- **Project number:** 5R01DK076629-13
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** James G Granneman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $463,992
- **Award type:** 5
- **Project period:** 2009-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376253

## Citation

> US National Institutes of Health, RePORTER application 10376253, Analysis of Lipolytic Trafficking in Adipocytes. (5R01DK076629-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10376253. Licensed CC0.

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