# Trib1 regulation of hepatic lipid metabolism and atherogenesis

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $402,500

## Abstract

PROJECT SUMMARY
Elevated plasma levels of lipoproteins containing apolipoprotein B (apoB), including low density lipoproteins
(LDL) and triglyceride-rich lipoproteins (TRL), are among the most important causal risk factors for
atherosclerotic cardiovascular disease (CVD). Despite major advances, the factors that regulate plasma levels
of apoB-containing lipoproteins remain incompletely understood. Furthermore, elevated levels of apoB-
containing lipoproteins, particularly TRL, are often associated with non-alcoholic fatty liver disease (NAFLD),
which is a major cause of end-stage liver disease but of which the pathophysiology remains poorly understood.
Unbiased `genome-wide' human genetics studies have identified a genomic 8q24 locus near the gene TRIB1
significantly associated with all major lipid traits (total cholesterol, LDL-C, HDL-C, TG), CVD, and liver enzymes,
making TRIB1 of high interest for functional evaluation. In vivo overexpression and loss-of-function mouse
studies have confirmed this association. Studies in mice with liver-specific deletion of Trib1 (Trib1_LSKO) have
shown that hepatic Trib1 not only regulates plasma lipids in mice, but also hepatic de novo lipogenesis, the
latter of which is accomplished via turnover of the transcription factor C/EBPα. Interestingly though, while
Trib1_LSKO mice exhibit increased plasma lipids, this appears to be due to a C/EBPα-independent
mechanism. Thus the underlying mechanism for hepatic Trib1 regulation of plasma lipids remains unclear. We
present evidence suggesting that increased expression of Angptl8 due to the absence of Trib1 may lead to
decreased hepatic clearance of apoB-containing lipoprotein particles. We propose to formally test this
hypothesis and to identify the downstream effector of Trib1 responsible for the increased Angptl8 expression.
Variants in the TRIB1 genomic locus are all significantly associated with CAD in humans, and while the effect
of Trib1 on plasma lipid levels is clear, no study to date has tested its implications for atherosclerosis.
Additionally, no role for extra-hepatic TRIB1 in atherogenesis has been investigated. Trib1 has been shown to
regulate the polarization of macrophages, and thus, the combination of its roles in liver and extrahepatic
tissues likely interplay in Trib1's overall contribution to risk for CAD. We will perform a deep phenotypic
analysis of atherosclerosis in mice that lack extrahepatic Trib1 (with and without rescue of liver Trib1
expression). Finally, while our mouse ChIP-Seq data indicates a negative feedback loop between Trib1 and
C/EBPα, (C/EBPα binds to downstream non-coding regions corresponding to the human GWAS signal), the
functional sequence variation linking TRIB1 and lipoprotein metabolism has yet to be identified. We will identify
the functional non-coding SNP underlying the TRIB1 GWAS signal though chromatin conformation capture,
and we will validate these functional SNPs with reporter assays and in iPS-derived hepatocyt...

## Key facts

- **NIH application ID:** 9836866
- **Project number:** 5R01HL134853-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Daniel James Rader
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2016-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836866

## Citation

> US National Institutes of Health, RePORTER application 9836866, Trib1 regulation of hepatic lipid metabolism and atherogenesis (5R01HL134853-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9836866. Licensed CC0.

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