# Lysosome-lipid droplet interactions in fatty acid metabolism

> **NIH NIH P20** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2022 · $221,271

## Abstract

An overload of cytosolic free fatty acids causes toxic effects termed lipotoxicity to cells and tissues and
thus has been recognized as a causative factor in many metabolic disorders, including non-alcoholic fatty
liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH). One source of
cytosolic free fatty acids is the lysosome, which releases free fatty acids after ingesting and digesting
endocytosed extracellular lipoproteins or after intracellular membranes and lipids are delivered to the
lysosome by autophagy. In principle, transport to and safe storage of free fatty acids in lipid droplets
protects cells, including liver cells, from lipotoxicity. Membrane contact sites (MCS) in general provide
vectorial transport of material between heterologous organelles and are increasingly appreciated for their
role in lipid homeostasis. However, it is not known whether MCS exist between lysosomes and lipid
droplets and whether such MCS may transport free fatty acids from lysosomes to lipid droplets. In our
preliminary studies, we have identified lysosome-lipid droplet MCS in human liver cells and defined the
protein-protein interactions at lysosome-lipid droplet MCS through genetic screening in yeast. The
objectives of the proposed project are to determine whether and how lysosome-lipid droplet MCS
transport free fatty acids, and whether promoting these MCS will prevent or reduce lipotoxicity and
ameliorate NAFLD progression. Our long-term goal is to develop intervention strategies for NAFLD
treatment based on the results of our studies proposed here. Three specific aims will be pursued:
1. Characterize lysosome-lipid droplet MCS and determine their role in free fatty acid transport.
2. Define the protein-protein interactions and delineate their roles at the lysosome-lipid droplet MCS.
3. Determine the role of lysosome-lipid droplet MCS in preventing lipotoxicity.
By delineating the features, mechanisms, and physiological functions of the lysosome-lipid droplet MCS,
the proposed studies will define the previously unappreciated interactions between lysosomes and lipid
droplets and uncover a novel mechanism of free fatty acid transport leading to their safe storage thereby
avoiding their toxicity. The proposed studies will deepen our understanding of fatty acid metabolism,
transport and storage, avoidance of free fatty acid lipotoxicity, and how these processes affect the
pathology of NAFLD and NASH. The characterized relationships and the specific proteins controlling
these processes will provide candidate targets for manipulation of the lysosome-lipid droplet MCS as a
potential intervention strategy in preventing NAFLD progression.

## Key facts

- **NIH application ID:** 10496983
- **Project number:** 2P20GM121176-06
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Jing Pu
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $221,271
- **Award type:** 2
- **Project period:** 2017-09-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10496983

## Citation

> US National Institutes of Health, RePORTER application 10496983, Lysosome-lipid droplet interactions in fatty acid metabolism (2P20GM121176-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10496983. Licensed CC0.

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