# Depalmitoylation regulates hepatic glucose metabolism

> **NIH NIH F30** · WASHINGTON UNIVERSITY · 2021 · $31,970

## Abstract

PROJECT SUMMARY/ABSTRACT
Hundreds of thousands of Americans are diagnosed with type 2 diabetes every year, increasing their risk of
developing cardiovascular disease and chronic kidney disease. While insulin signaling in the liver typically
modulates blood glucose levels by suppressing the synthesis of new glucose and inducing glucose storage,
hepatic insulin resistance can exacerbate hyperglycemia. Insulin resistance is associated with dysregulated
fatty acid metabolism. Fatty acids can directly modify proteins through a reversible process known as
palmitoylation. Depalmitoylating acyl protein thioesterases (APTs), such as APT1 and APT2, can remove these
posttranslational modifications. Although multiple proteins involved in glucose homeostasis have been shown
to be palmitoylated, the role of depalmitoylases in metabolism is still under investigation. Preliminary data
suggest that APT1 liver knockout (APT1LKO) female mice have insulin resistance, while APT2LKO female
mice demonstrate increased fasting plasma glucose levels. However, the redundancy of APT1 and APT2 in
the glucose metabolic pathway is unclear. The objective of this proposal is to elucidate the mechanisms and
consequences of functional redundancy of APT1 and APT2 in the context of glucose homeostasis. The overall
hypothesis is that depalmitoylation by both APT1 and APT2 regulates hepatic glucose metabolism. Aim 1 of
this proposal will determine the substrate redundancy of APT1 and APT2 using in vitro proximity labeling. This
aim will generate APT-biotin ligase fusion constructs to label proteins proximal to APT1 and APT2. Mass
spectrometry of biotinylated proteins will facilitate identification of shared APT-protein interactions. Aim 2 of this
proposal will investigate the functional redundancy of APT1 and APT2 in murine hepatic glucose metabolism.
Chow- and high fat-fed mice with dual deletion of hepatic APT1 and APT2 will be tested for glucose, insulin,
and pyruvate tolerance. Hepatic insulin signaling will also be evaluated in single and double liver-KO mice. The
long-term goal of the proposed research is to implicate reversible lipid modifications in the development of
metabolic disease.
During the fellowship, the applicant will develop important skills for becoming an independent investigator of
metabolism, emphasizing cellular and molecular biology techniques. The sponsor of this work, Dr. Clay
Semenkovich, has vast experience studying the relationship between fatty acid and glucose metabolism, and
the institutional environment provides supportive, collaborative experts in liver physiology and molecular
biology. Washington University School of Medicine has a long history of helping physician-scientists build
successful careers. The proposed training plan will facilitate the applicant’s transition into becoming an
independent physician-scientist, using research to discover novel targets for treating chronic metabolic
diseases.

## Key facts

- **NIH application ID:** 10387053
- **Project number:** 1F30DK131830-01
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Sarah Lilly Speck
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $31,970
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10387053

## Citation

> US National Institutes of Health, RePORTER application 10387053, Depalmitoylation regulates hepatic glucose metabolism (1F30DK131830-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10387053. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*