# Regulation of Lipid Droplet Biogenesis and Lipophagy

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $330,750

## Abstract

ABSTRACT
Metabolic diseases are a pressing public health issue in the United States. With the meteoric rise of insulin
resistance, obesity, and atherosclerosis, mechanistic understanding of lipid metabolism could not be more
imperative. Many of these metabolic disorders involve improper storage of lipids into cellular lipid storage
organelles known as lipid droplets (LDs). These unique organelles, which contain a core of triacylglycerols and
cholesterol esters, accumulate when dietary free fatty acids are abundant, and conversely get consumed when
there is a high demand for energy. In this way, LDs are essential for both cellular and whole-body
homeostasis. Proteins that reside on the surface of LDs play critical roles in the dynamic turnover of LDs by
controlling the intake and release of the lipids stored within. Although the metabolic roles of LDs are well
known, the mechanisms employed to regulate the growth and catabolism of individual LDs are poorly
understood. We have identified two proteins, DFCP1 and WHAMM, which are poised to function as crucial
metabolic switches for LDs. In particular, we found that DFCP1 localizes to compartments that are involved in
both LD biogenesis and catabolism. Moreover, we discovered that DFCP1 has unique biochemical properties
that allow it to form an oligomeric coat on LDs, which suggests that it could play a role in the tethering of LDs to
the ER and other LDs. Forcing DFCP1 to disassemble from LDs leads to misregulated LD catabolism. Thus,
we postulate that DFCP1 functions as a molecular switch that releases growing LDs from the ER for
catabolism. Interestingly, LD release is coupled to the accumulation of the activator of the Arp2/3 complex,
WHAMM, and actin. We found that accumulation of WHAMM and actin to LDs occurs specifically in response
to starvation, where it drives actin-mediated mobilization and constriction of LDs. Consequently, the goals of
this proposal are to define the molecular mechanisms employed by DFCP1, WHAMM, and the actin
cytoskeleton to drive LD catabolism. To fully address these questions, we will use a bottom-up approach to
determine the mechanism and molecular properties that allow DFCP1 to switch LDs from growth to catabolism
(Aim 1). In parallel, we will examine how WHAMM and the Arp2/3 complex coordinate with DFCP1 to drive LD
dynamics and catabolism (Aim 2). The mechanistic insight obtained by these studies will provide new insights
into how LD metabolism helps to maintain cellular homeostasis, but also how misregulation of this process
contributes to the pathogenesis of metabolic diseases.

## Key facts

- **NIH application ID:** 10375405
- **Project number:** 5R01GM136925-03
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** DAVID J KAST
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $330,750
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375405

## Citation

> US National Institutes of Health, RePORTER application 10375405, Regulation of Lipid Droplet Biogenesis and Lipophagy (5R01GM136925-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375405. Licensed CC0.

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