# Lipid Droplets and Transcriptional Regulation of Metabolism

> **NIH NIH R01** · HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH · 2022 · $470,023

## Abstract

Abstract
Lipid storage is a fundamental process for organisms to buffer fluctuations in the availability and need for
metabolic energy. Lipids are predominantly stored as neutral lipids, such as triacylglycerols (TGs), in
organelles called lipid droplets (LDs). In conditions of excess metabolic energy, cells convert carbohydrates
to fatty acids and esterify them, along with dietary fatty acids, to glycerol-3-phosphate to form TG.
Conversely, when fatty acids are needed as metabolic fuel or as precursors for membrane components,
TGs are hydrolyzed. Whether or not cells have lipid stores directly impacts their ability to grow and divide,
as well as their physiology and need to import nutrients. Through a combination of unbiased genetic and
biochemical screens, we recently found that all members of the MLX family of transcription factors localize
to the LD surfaces as LDs accumulate in cells. These transcription factors include MLX and its obligate
dimerization partners, MLXIP/MondoA or MLXIPL/MondoB/ChREBP, which detect glucose derivatives and
are key regulators of glucose and lipid metabolism. Deficiency of ChREBP has also been linked to the
developmental disorder Williams-Beuren syndrome and to features of the metabolic syndrome.
Based on extensive preliminary data, we suggest a model in which the accumulation of LDs serves to
attenuate the transcriptional response of MLX:ChREBP or MLX:MondoA targets in response to glucose.
We will test this model defining the mechanism and regulation of MLX-type transcription factor targeting to
LDs and elucidating how this modulates their response to glucose.
Completing these aims will reveal a fundamental aspect of metabolic coordination through a fascinating,
novel paradigm of transcriptional control. It may also have important implications for human health.
Overaccumulation of LDs is the hallmark of metabolic disease linked to obesity, a problem of pandemic
proportions. Our findings will shed new light on physiological sequelae of LD accumulation, possibly
providing therapeutic avenues for intervention.

## Key facts

- **NIH application ID:** 10356853
- **Project number:** 5R01DK124913-03
- **Recipient organization:** HARVARD UNIVERSITY D/B/A HARVARD SCHOOL OF PUBLIC HEALTH
- **Principal Investigator:** ROBERT V FARESE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $470,023
- **Award type:** 5
- **Project period:** 2020-04-01 → 2022-09-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10356853

## Citation

> US National Institutes of Health, RePORTER application 10356853, Lipid Droplets and Transcriptional Regulation of Metabolism (5R01DK124913-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10356853. Licensed CC0.

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