# Molecular Mechanisms of TRIB1 Regulation of Hepatic Metabolism

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $97,851

## Abstract

PROJECT SUMMARY
The 8q24 genomic locus, containing the gene Tribbles pseudokinase 1 (TRIB1) has been repeatedly linked via
human genome-wide association study with multiple cardiometabolic parameters. This includes plasma total
cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, coronary artery disease (CAD), circulating liver
enzymes and non-alcoholic fatty liver disease (NAFLD), circulating adiponectin, and HbA1c. Despite the genetic
evidence supporting a role for this gene in human disease and early observations underscoring the importance
of hepatic Trib1, mechanistic studies of this gene have lagged. In the parent application, we presented
preliminary data demonstrating that hepatic TRIB1 promotes COP1-dependent ubiquitination of the transcription
factor C/EBPα, and this process requires a novel interaction with a different pseudokinase, STK40. Additionally,
we established multiple in vivo animal models to test the therapeutic potential of increased hepatic Trib1 activity
in animal models of metabolic disease. Finally, we utilized whole exome sequencing in a highly novel
consanguineous population to identify predicted loss-of-function (pLoF) variants in TRIB1 that can help
determine its function in humans. This parent award experimental plan aims to address the following specific
aims: 1) To determine how hepatic TRIB1-mediated ubiquitination of target proteins is regulated by STK40; 2)
To determine the therapeutic benefit of Trib1 overexpression in animal models of CAD and NAFLD, and the
requirement for C/EBPα for such benefits; and 3) To determine the direction of effect and therapeutic potential
for TRIB1 through the identification and metabolic phenotyping of subjects harboring TRIB1 pLoF variants. This
diversity supplement expands the scope of aim 3 from the parent award by investigating pLoF variants identified
in CEBPA. As this is the major downstream target of TRIB1, the identification of pLoF C/EBPα proteins can help
elucidate the function of the TRIB1-C/EBPα hepatic regulatory axis in human physiology and disease. During
this diversity supplement, the candidate will test the functional effects of pLoF CEBPA variants via the following
in vitro and in vivo techniques: 1) generate recombinant mutant CEBPA cDNA constructs containing rare pLoF
mutations and test their ability to activate a custom C/EBPα-responsive luciferase reporter, and 2) generate AAV
plasmid constructs of mutant CEBPA to test the ability of these to induce steatosis in wild-type mice and rescue
the phenotype of mice with hepatic Cebpa deletion. The completion of these studies will add to our understanding
of the role of the TRIB1-C/EBPα regulatory axis in human hepatic metabolism and help elucidate the therapeutic
potential of TRIB1. These studies will also further our understanding of the mechanistic underpinnings of the
myriad genetic associations with the TRIB1 gene in humans. Our ultimate goal is an in depth understanding of
the functions of hepatic TR...

## Key facts

- **NIH application ID:** 11047206
- **Project number:** 3R01DK134026-02S1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Robert Clayton Bauer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $97,851
- **Award type:** 3
- **Project period:** 2023-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11047206

## Citation

> US National Institutes of Health, RePORTER application 11047206, Molecular Mechanisms of TRIB1 Regulation of Hepatic Metabolism (3R01DK134026-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11047206. Licensed CC0.

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