# The molecular basis for the role of apolipoprotein A-II in cholesterol and triglyceride metabolism

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2022 · $498,218

## Abstract

Apolipoprotein (apo)A-II is an abundant human plasma protein primarily in high-density
lipoproteins (HDL) but also in very low density lipoproteins (VLDL) and chylomicrons. Despite
a large literature, its physiological functions remain ambiguous and widely debated. For
example, it has been postulated to play both beneficial and detrimental roles in cardiovascular
disease (CVD) development. We believe that apoA-II functions quite differently than other
apolipoproteins, which tend to act directly as a co-factor or ligand. We hypothesize that apoA-
II impacts both HDL and VLDL metabolism indirectly by altering the lipoprotein proteome
and/or affecting the conformation and function of co-residing proteins. Our work shows that
apoA-II can stimulate HDL to promote cholesterol efflux from cells, but only when apoA-I is
present. This is important because HDL cholesterol efflux proficiency is a better predictor of
cardiovascular disease (CVD) than its plasma levels. We also found that apoA-II impacts the
VLDL proteome and suspect that this underlies delayed VLDL lipolysis and/or receptor
mediated clearance when apoA-II is elevated. Hypertriglyceridemia and delayed post-
prandial remnant clearance is an important CVD risk factor. We will define the mechanism for
apoA-II’s potentiation of HDL-mediated cholesterol efflux by testing its effects on apoA-I
structure using innovative structural techniques including cryo-electron microscopy. An
important goal will be to identify the apoA-II sequences responsible with an eye toward
developing cholesterol efflux boosting therapeutics. Using human proteins in human plasma-
based experiments, we will also determine how apoA-II affects the composition and structure
of other VLDL proteins and assess the consequences with respect to activation of lipoprotein
lipase and binding to cell surface receptors responsible for its plasma clearance. With a full
mechanistic understanding of these effects, it may be possible to derive apoA-II based
therapeutic approaches that minimize the protein’s deleterious effects while optimizing
benefits for CVD and possibly other metabolic diseases.

## Key facts

- **NIH application ID:** 10318588
- **Project number:** 5R01HL155601-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** W Sean Davidson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $498,218
- **Award type:** 5
- **Project period:** 2020-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318588

## Citation

> US National Institutes of Health, RePORTER application 10318588, The molecular basis for the role of apolipoprotein A-II in cholesterol and triglyceride metabolism (5R01HL155601-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10318588. Licensed CC0.

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