# Regulation of lipoprotein metabolism by adipose-specific Tribbles-1

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $400,000

## Abstract

Cardiovascular disease (CVD) remains the leading cause of mortality in the western world despite the
widespread success of statins. Genome-wide association studies (GWAS) have identified hundreds of genomic
loci as significantly associated with plasma lipoprotein traits and coronary artery disease (CAD) in humans, many
of which contain genes not previously implicated in metabolic disease pathogenesis. These loci could represent
novel disease biology and new avenues for therapeutic intervention in CVD. The 8q24 locus, harboring the gene
Tribbles-1 (TRIB1), is one of only two loci to associate with all plasma lipid traits (total cholesterol, LDL-C, HDLC,
triglycerides (TG)) and CAD, yet little is known about the mechanisms governing those associations.
Interestingly, TRIB1 significantly associates with plasma adiponectin levels as well, suggesting that TRIB1 has
a role in adipose biology. We present here data that mice with adipose-specific knockout of Trib1 (Trib1_ASKO)
have decreased plasma cholesterol and triglycerides, and increased circulating adiponectin. Preliminary
investigations suggest that this finding is due in part to reduced hepatic cholesterol synthesis. Thus, it appears
that adipose Trib1 affects hepatic lipid metabolism via crosstalk between the liver and adipose. This is consistent
with the observation that Trib1_ASKO mice have altered adipokine secretion, yet previous work suggests that
the cholesterol reduction observed in the Trib1_ASKO mice is likely adiponectin independent. How Trib1 effects
adipokine secretion is unknown, and despite the established relationship between TRIB1 and the transcription
factor C/EBP itself an important regulator of adipogenesis, our preliminary data suggests that the effects of
Trib1 in the adipocyte are C/EBP-independent. Finally, the altered plasma lipid profile in the Trib1_ASKO mice
suggests that adipose TRIB1 regulates plasma lipoprotein metabolism, and thus it follows that the GWAS SNPs
near TRIB1 likely affect the function of adipose-specific TRIB1, presumably through altered gene expression.
Currently, little is known about the regulation of TRIB1 expression in adipose and the effects of common variation
on this regulation. In this proposal, I outline a strategy for determining the cause of altered plasma lipids in
Trib1_ASKO mice, the function of adipocyte TRIB1, and the adipose-specific effect of non-coding variation near
TRIB1. I will accomplish these goals using genetically modified animal models, in vitro and ex vivo cell culture,
AAV-mediated somatic gene manipulation, genome editing with CRISPR/Cas9, and human induced-pluripotent
stem cells. TRIB1 remains one of the most interesting genes to arise from plasma lipid and CAD GWAS studies,
given the constellation of traits it associates with. The studies outlined in this proposal promise to elucidate novel
functions of both this protein in adipose, and for adipose in regulating hepatic lipoprotein metabolism. These
studies will furt...

## Key facts

- **NIH application ID:** 9892881
- **Project number:** 5R01HL141745-03
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Robert Clayton Bauer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $400,000
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892881

## Citation

> US National Institutes of Health, RePORTER application 9892881, Regulation of lipoprotein metabolism by adipose-specific Tribbles-1 (5R01HL141745-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9892881. Licensed CC0.

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