# Mechanisms regulating the atherogenic activities of serum amyloid A

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2021 · $501,577

## Abstract

Acute phase serum amyloid A (SAA) is not only predictive of cardiovascular disease events (CVD) but also
plays a causal role in the development of atherosclerosis. SAA is a family of secreted proteins whose
concentration in the plasma increases 1000-fold or more during a systemic inflammatory response before
returning to near undetectable levels. However, SAA is also persistently elevated in chronic inflammatory
conditions such as diabetes, obesity, rheumatoid arthritis, etc. While the liver is the major source of SAA
during an acute inflammatory response, extra-hepatic expression has also been documented. Most notably,
adipose tissue is thought to be an important source of systemic SAA in obese humans. It has been recognized
for decades that plasma levels of SAA predict cardiovascular risk in humans. More recently, our group
determined that SAA plays a causative role in atherosclerosis in apoE-deficient mice. According to numerous
reports by multiple laboratories, SAA exerts a myriad of effects in vitro that would be expected to exacerbate
inflammation and atherosclerosis in vivo. However, most of these published studies investigated lipid-free SAA,
overlooking the fact that lipid-free SAA is not detected in the circulation. In most circumstances, plasma SAA is
found associated with the high-density lipoprotein (HDL) fraction, and accumulating evidence demonstrates
that HDL inhibits SAA’s pro-inflammatory activity. Thus, one function of HDL may be to sequester and
neutralize SAA and limit the propagation of inflammation in vivo. Notably, SAA can also be detected on apoB
particles, particularly in human populations with increased risk for cardiovascular disease. Although the
pathophysiological significance of the association of SAA with non-HDL lipoproteins is not known, we have
shown that SAA on apoB-containing lipoproteins augments their proteoglycan binding, which could lead to
increased vascular retention. Taken together, these observations lead us to propose that the pro-
inflammatory/pro-atherogenic activities of SAA are regulated by factors that influence the equilibrium between
HDL-SAA, very low-density lipoprotein/low-density lipoprotein-SAA, and lipid-free SAA. To test this hypothesis,
we have developed critical research tools, including novel mouse models with inducible, tissue-specific SAA
expression, to achieve three comprehensive and interactive aims: Aim 1) Determine whether HDL remodeling
factors (e.g., cholesterol ester transfer protein, phospholipase A2 and oxidation) leads to the release of
bioactive SAA from SAA-enriched HDL; Aim 2) Determine whether the association of SAA on apoB
lipoproteins increases their atherogenicity in vitro and in vivo; and Aim 3) Determine if the tissue source of SAA
(liver versus adipose tissue) influences its lipoprotein distribution and/or its pro-atherogenic effects in vivo. The
results of this proposal will validate SAA as a therapeutic target in cardiovascular disease, and will develop
SAA lipo...

## Key facts

- **NIH application ID:** 10210327
- **Project number:** 5R01HL147381-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Preetha Shridas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $501,577
- **Award type:** 5
- **Project period:** 2020-07-05 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210327

## Citation

> US National Institutes of Health, RePORTER application 10210327, Mechanisms regulating the atherogenic activities of serum amyloid A (5R01HL147381-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10210327. Licensed CC0.

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