# Regulation of GPIHBP1-dependent and independent triglyceride clearance

> **NIH NIH R01** · UNIVERSITY OF IOWA · 2020 · $381,250

## Abstract

PROJECT SUMMARY
Clinical hypertriglyceridemia is common and is only partially responsive to available drugs. Conversely,
excess triglyceride delivery to individual tissues can lead to skeletal muscle insulin resistance, cardiac
lipotoxicity, or severe inflammatory responses. Given the importance of proper triglyceride delivery, it is
imperative that we understand the mechanisms that regulate this process. Two proteins normally
required for triglyceride clearance are lipoprotein lipase (LPL) and GPIHBP1. LPL is required for the
actual hydrolysis of plasma triglyceides, liberating fatty acids for tissue uptake. The endothelial cell
protein GPIHBP1 is required to properly localize LPL to the vascular lumen where lipolysis takes place.
The long term goal of the proposed research is to understand and ultimately modulate the delivery of
triglyceride-derived fatty acids to specific tissues. The objectives in this application are to advance our
understanding of how the angiopoietin-like (ANGPTL) proteins, ANGPTL3 and ANGPTL4, modulate
triglyceride clearance. ANGPTL3 and ANGPTL4 can both inhibit LPL in vitro, and ANGPTL3 or
ANGPTL4 deficiency leads to lower plasma triglyceride levels. However, if and how ANGPTL3 and
ANGPTL4 directly modulate LPL/GPIHBP1-mediated triglyceride clearance is not clear. Moreover, the
plasma triglyceride levels in mice deficient in both GPIHBP1 and ANGPTL4 indicate that ANGPTL4 may
regulate an uncharacterized, GPIHBP1-independent triglyceride clearance pathway. These issues will be
addressed by pursuing two specific aims: 1) Define the mechanisms by which ANGPTL3 and ANGPTL4
modulate GPIHBP1-dependent triglyceride clearance; and 2) Identify novel mechanisms of GPIHBP1-
independent triglyceride clearance. The studies in aim 1 employ cell culture–based binding and lipase
activity assays, as well as in vivo injection of recombinant proteins and tissue-specific knockout mice to
investigate how ANGPTL proteins interact with GPIHBP1/LPL complexes on the surface of endothelial
cells. The second aim will address the remarkably lower triglycerides in Angptl4–/–Gpihbp1–/– mice.
Triglyceride clearance and fatty acid uptake assays will be used to identify the tissues to which
triglycerides get cleared. Expression, protein, and lipase activity analysis will be used to identify the
proteins responsible for this clearance. The approaches in the proposed research are innovative
because they combine standard methods with novel mouse models to address previously untested
questions about how triglyceride clearance is regulated. The proposed studies are significant because
they will elucidate how and where ANGPTL3 and ANGPTL4 modulate levels of functional LPL to
influence triglyceride delivery and will uncover novel mechanisms of triglyceride clearance that do not
require vascular LPL, ultimately permitting new strategies designed to prevent or treat dyslipidemia.

## Key facts

- **NIH application ID:** 9895855
- **Project number:** 5R01HL130146-05
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** BRANDON Scott Joseph DAVIES
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2016-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895855

## Citation

> US National Institutes of Health, RePORTER application 9895855, Regulation of GPIHBP1-dependent and independent triglyceride clearance (5R01HL130146-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9895855. Licensed CC0.

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