# Lipid sensing through G protein geranylgeranylation

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $335,900

## Abstract

Project Summary/Abstract
Lipid signaling plays a critical role in the regulation of organismal physiology and metabolic expenditure.
Imbalances in lipid homeostasis can deleteriously impact health and cells within the organism tightly regulate
lipid absorption, synthesis and metabolism to accommodate energetic demands and ensure energetic reserves
later in life. Cells stockpile energy reserves under ample metabolic resources through SREBP-regulated
lipogenesis. Yet, less clear is how cells regulate lipid homeostasis under nutrient depleted conditions and in
particular, how cells sense metabolic demand and respond by increasing nutrient absorption. Our examination
of several lipid depletion paradigms in C. elegans has identified a highly responsive small G protein, RAB-11.2,
which is transcriptionally activated upon defects in the isoprenoid/mevalonate synthesis pathway. Through
further investigation, we have discovered a new mechanism linking the nucleocytoplasmic dynamics of the
nuclear hormone receptor, NHR-49, with nutrient absorption through RAB-11.2.
Through the proposed five-year research period, we aim to define the molecular mechanism by which cells sense
and respond to their need for de novo lipid synthesis. Our preliminary data suggests that cells sense their
capacity to breakdown lipids through monitoring the availability of a particular prenol lipid synthesized through
the isoprenoid pathway, geranylgeranyl pyrophosphate. Under conditions of high homeostatic lipid levels,
geranylgeranylation of RAB-11.1 enables it to bind and sequester NHR-49 to cytosolic transport vesicles in a
transcriptionally inactive state. Under lipid limited conditions caused by starvation or defective lipolysis/β-
oxidation, cells lack the resources to synthesize GGPP through the isoprenoid pathway, which prevents RAB-
11.1 from binding vesicles and disrupts endocytic recycling pathways required for nutrient absorption. Due to the
inability of its RAB-11.1 binding partner to associate with vesicles, NHR-49 is release from cytosolic vesicles and
translocates to the nucleus where it activates transcription of several metabolic enzymes, nutrient transporters
and RAB-11.2 to re-establish nutrient absorption.

## Key facts

- **NIH application ID:** 10769809
- **Project number:** 5R01AG076529-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Peter Mahan Douglas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $335,900
- **Award type:** 5
- **Project period:** 2022-05-15 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10769809

## Citation

> US National Institutes of Health, RePORTER application 10769809, Lipid sensing through G protein geranylgeranylation (5R01AG076529-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10769809. Licensed CC0.

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