# Investigating the role of PHD3 in lipid homeostasis

> **NIH NIH R01** · HARVARD MEDICAL SCHOOL · 2022 · $423,750

## Abstract

Project Summary
Adaptation of cellular metabolism is crucial for maintaining tissue and whole-body homeostasis. In
response to low energy or stress, cells activate AMP-activated protein kinase (AMPK) to phosphorylate
acetyl-CoA carboxylase (ACC), which increases mitochondrial fatty acid oxidation (FAO) and ATP
levels. However, how FAO is downregulated in energy abundance states is not fully understood. As
pathways that drive fuel addiction may provide new therapeutic targets or biomarkers for personalized
therapy, there is a critical need to identify pathways that regulate metabolic homeostasis. We have
discovered a new nutrient-dependent signaling pathway that controls fat oxidation via a little studied
member of the prolyl hydroxylase domain protein family, PHD3. PHDs are a family of -ketoglutarate
dependent dioxygenases that hydroxylate substrate proline residues and have been linked to fuel
switching. We find that PHD3 regulates fatty acid metabolism by hydroxylating acetyl-CoA carboxylase
(ACC2), a regulator of mitochondrial FAO. In response to nutrient abundance, PHD3 activates ACC2
to inhibit catabolism of fatty acids. Since ACC2 and PHD3 are highly expressed in oxidative tissues
such as skeletal muscle, this proposal will test the hypothesis that the loss of PHD3 in skeletal muscle
deregulates energy homeostasis by preventing ACC2 hydroxylation, hence causing constitutive
mitochondrial oxidative metabolism. This proposal will test these ideas by: 1) defining the kinetics and
determining the specificity by which PHD3-mediated hydroxylation regulates ACC2, 2) defining the role
of PHD3 in nutrient signaling in skeletal muscle cell energetics, and 3) testing the physiological
relevance of PHD3 in muscle energy homeostasis in vivo. First, we will utilize recombinant purified
PHD3 to quantify the kinetic parameters of PHD3 hydroxylation of ACC2 versus HIF1. Next we will
examine the specificity of ACC2 hydroxylation by PHD1-3 (Aim 1). We will also examine the effect of
PHD3 on cellular metabolism in skeletal muscle cells in response to nutrient cues. We will examine the
necessity of AMPK, ACC2, and HIF1 signaling on the metabolic roles of PHD3 (Aim 2). Finally, we will
examine the consequences of PHD3 activity on skeletal muscle physiology in a resting state and during
acute energy challenge (Aim 3). Our overarching goal is to elucidate the molecular elements of PHD3
signaling that control cellular metabolism and to leverage these findings to ultimately develop
therapeutic strategies to promote improved muscle function and metabolic fitness.

## Key facts

- **NIH application ID:** 10430260
- **Project number:** 5R01DK127278-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** MARCIA HAIGIS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430260

## Citation

> US National Institutes of Health, RePORTER application 10430260, Investigating the role of PHD3 in lipid homeostasis (5R01DK127278-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10430260. Licensed CC0.

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