# Role of alpha-catenin and Wnt signaling in regulating lipid homeostasis

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $443,700

## Abstract

Title: Role of α-catenin and Wnt signaling in regulating lipid homeostasis
Project Summary:
Wnt signaling, normally limited to embryogenesis, stem cell renewal and wound healing, is inappropriately re-
employed in a variety of human cancers, such as hepatocellular carcinoma and colorectal cancer, as well as
other diseases. Aberrant Wnt signaling and altered lipid metabolism are both signs of oncogenesis, and recent
data suggest that Wnt control of adipogenesis and lipid metabolism may occur through separate mechanisms.
Currently, the mechanisms remain poorly understood, and so remain outside of our ability to monitor, mitigate,
prevent, or correct. It has been impossible to clearly delineate separate functions of Wnt in adipogenesis, lipid
anabolism, and lipid catabolism, because these processes are inextricably interconnected in mammals. To
circumvent this limitation, we use Drosophila as a primary experimental system, which provides unparalleled
sophistication in manipulating Wnt (Wingless in Drosophila) activity in vivo. More importantly, the unique
temporal separation of adipogenesis, lipogenesis, lipolysis, and fatty acid β-oxidation during the Drosophila life
cycle allows us to precisely monitor and manipulate these fundamental processes. Our genetic analyses of
Axin and α-catenin, two components of the Wnt signaling pathway, have revealed that Wnt signaling regulates
lipid homeostasis during the late larval stage, separately from adipogenesis completed during embryogenesis.
We have confirmed that the phenotypes of Axin mutants are caused by a gain of the canonical Wnt activity,
elevated expression of β-catenin target genes, and altered expression of genes encoding enzymes involved in
lipid catabolism. By screening a library of diverse FDA-approved drugs, we discovered that both the defective
lipid homeostasis and the hyperactive Wnt signaling are potently suppressed by peptide boronic acids, a class
of proteasome inhibitors. The suppressive effects of these inhibitors are dependent on α-catenin. Despite the
important role of α-catenin in Wnt signaling, the precise mechanisms that normally regulate the stability of α-
catenin remain unclear. Thus the objective of this proposal is to determine how α-catenin stability in particular,
and Wnt signaling in general, regulates lipid catabolism. We will identify the molecular and cellular
mechanisms that control the stability of α-catenin in Drosophila by analyzing fat deposition and lipid
accumulation. Our investigations will define the molecular mechanism(s) that control the stability of α-catenin
and reveal how Wnt signaling regulates lipid mobilization and lipid catabolism, thereby advancing our
understanding of the tumor suppressive effects of α-catenin and how Wnt signaling regulates lipid homeostasis.

## Key facts

- **NIH application ID:** 10375985
- **Project number:** 7R01GM129266-04
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** Jun-yuan Ji
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $443,700
- **Award type:** 7
- **Project period:** 2018-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375985

## Citation

> US National Institutes of Health, RePORTER application 10375985, Role of alpha-catenin and Wnt signaling in regulating lipid homeostasis (7R01GM129266-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10375985. Licensed CC0.

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