# Lysophosphatidic acid and cardiovascular disease risk

> **NIH VA I01** · VA MEDICAL CENTER - LEXINGTON, KY · 2021 · —

## Abstract

Veterans have a higher incidence of cardiovascular disease than the general population. Cardiovascular
disease risk is caused by environmental and heritable factors. The broad goal of our research is to understand
how these factors interact to determine overall disease risk. In current funding period of this award we studied
how heritable variants of the PLPP3 gene encoding lipid phosphate phosphatase 3 (LPP3) associate with
heritable coronary artery disease risk. We showed that disease risk associated loci within the final intron of the
gene decrease expression of the gene in blood and vascular cells and that PLPP3 deficiency in mice results in
accelerated atherosclerosis. Our findings support the concept that PLPP3 functions as an “atherosclerosis
suppressor” gene and that heritable variants that decrease expression of the gene promote heart disease risk.
LPP3 is an integral membrane cell surface enzyme that can dephosphorylate and inactivate bioactive lipid
mediators. One of these LPP3 substrates, lysophosphatidic acid (LPA) acts on multiple blood and vascular
cells to promote inflammation and cardiovascular disease progression. In mice, genetic or pharmacological
targeting of LPA modulates atherosclerosis. In our mouse studies, LPP3 deficiency was associated with
increased levels of LPA in the blood and vascular tissues. These results support our overarching hypothesis
that dephosphorylation and inactivation of LPA underlies the normally protective effect of LPP3 on
cardiovascular disease focusing attention on the sources of bioactive LPA in the blood and vasculature. In
preliminary studies we found that circulating levels of LPA are very sensitive to diet in mice and humans. This
diet sensitive pool of LPA is largely associated with atherogenic lipoproteins that are formed in the intestine
from dietary fats and lipids (chylomocrons and their remnants) or are made in the liver (low density
lipoproteins). LPA in blood plasma can be made from lysoglycerophospholipids by autotaxin (ATX) which is a
secreted lysophospholipase D enzyme supporting the hypothesis that exogenous and endogenous sources of
circulating LPA come from lysophospholipids that are formed in the intestine or the liver. LPA is also an
intermediate in the synthesis of triglycerides by the intestine and liver so, since this process is coupled to the
generation of these atherogenic lipoproteins it is also possible that plasma LPA is generated de novo. The first
aim of this proposal will test these competing hypotheses directly by using stable isotope tracers and mass
spectrometry studies in mice and humans to directly identify precursors of circulating LPA. The mouse studies
will allow us to use genetic and pharmacological approaches to selectively manipulate ATX, LPP3 and the
formation and clearance of intestinal and hepatic derived lipoproteins. Atherogenic lipoproteins elicit signaling
responses in blood and vascular cell types that underlie the initiation and progression of ca...

## Key facts

- **NIH application ID:** 9858243
- **Project number:** 5I01CX001550-08
- **Recipient organization:** VA MEDICAL CENTER - LEXINGTON, KY
- **Principal Investigator:** ANDREW J MORRIS
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-01-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858243

## Citation

> US National Institutes of Health, RePORTER application 9858243, Lysophosphatidic acid and cardiovascular disease risk (5I01CX001550-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9858243. Licensed CC0.

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