# Project 2: Regulation of lipid and glucose metabolism by ANGPTL3 in humans

> **NIH NIH P01** · UNIVERSITY OF WASHINGTON · 2020 · $483,871

## Abstract

Human genetic, epidemiologic, and randomized clinical trial data suggest that therapies that independently
lower LDL-C and TRLs reduce the risk of CVD. Inhibiting ANGPTL3 recently emerged as a novel therapeutic
approach for reducing both LDL-C and TRLs, which, unlike other lipid-lowering therapies, may protect against
diabetes because ANGPTL3-deficient subjects have improved insulin sensitivity. However, the complete
metabolic consequences of inhibiting ANGPTL3 in humans and the cellular mechanisms responsible for the
cardiometabolic protective effect of ANGPTL3 deficiency remain unknown. In that context, Project 2’s aims will
define the role of ANGPTL3 in lipid and glucose metabolism. Aim 1 will determine how ANGPTL3 deficiency
alters lipoprotein and glucose metabolism in humans, using in vivo tracer kinetic studies in controls and in a
previously recruited family with participants who have either single or biallelic ANGPTL3 loss of function
mutations. We will determine how ANGPTL3 deficiency alters fasting and postprandial plasma lipoprotein
particle number, size, and composition in addition to adipose tissue and skeletal muscle transcriptional
programs related to glucose metabolism. Aim 2 will use subject-specific iPSCs from humans with complete
ANGPTL3 deficiency along with corrected isogenic control iPSCs to determine the cellular mechanisms linking
ANGPTL3 with lipoprotein (including RLP) and glucose metabolism. Unlike the therapeutic targets of APOB
(mipomerson) and MTTP (lomitapide), ANGPTL3 deficiency appears to reduce hepatic VLDL secretion without
leading to hepatic steatosis. In addition, unlike other approved LDL-lowering therapies (statins, PSCK9
inhibitors, etc), ANGPTL3 deficiency appears to reduce LDL cholesterol without worsening risk for T2DM.
Together, these observations suggest that ANGPTL3 may be working through novel intracellular and
extracellular pathways that are yet to be discovered which collectively modulate lipoprotein and glucose
metabolism. The studies outlined here are poised to discover these cellular mechanisms which hold the
promise to expand our understanding of human biology and identify additional therapeutic targets for the
treatment of dyslipidemia while improving glucose levels.

## Key facts

- **NIH application ID:** 9934534
- **Project number:** 1P01HL151328-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Nathan Oliver Stitziel
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $483,871
- **Award type:** 1
- **Project period:** 2020-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934534

## Citation

> US National Institutes of Health, RePORTER application 9934534, Project 2: Regulation of lipid and glucose metabolism by ANGPTL3 in humans (1P01HL151328-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934534. Licensed CC0.

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