# PPAR-gamma Deacetylation in Cardiometabolic Disease

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $546,810

## Abstract

ABSTRACT
Reducing the incidence, severity, and complications of atherosclerotic cardiovascular (CV) disease in type 2
diabetes remains a key unmet medical need. Insulin resistance predisposes to atherosclerosis and worsens its
macrovascular complications in patients with type 2 diabetes. While new anti-hyperglycemic drugs offer
glimmers of hope to reduce the risk of CV events in diabetes, the relative disease burden remains large. Thus,
treatments that address other aspects of diabetes pathogenesis, most notably insulin resistance, are needed.
Interest in the effects of insulin sensitizers on atherosclerosis was rekindled by a recent study showing that the
thiazolidinedione (TZD) insulin-sensitizer, pioglitazone, reduced the recurrence risk of cerebrovascular events in
insulin-resistant patients with a recent ischemic stroke or transient ischemic attack. However, use of these
agents is marred by serious adverse events, including worsening of congestive heart failure, fractures, and
bladder cancer. In studies supported by this PPG, Drs. Accili and Qiang have shown that TZDs regulate the
function of their target PPARg by deacetylating two amino acid residues, K268 and K293. They demonstrated
that TZD-dependent deacetylation of PPARg modulates the latter’s ability to activate or repress target genes. In
preliminary data, they show that mice homozygous for knock-in alleles of PPARg resulting in its constitutive
deacetylation (K268R and K293R, thus 2KR) maintain the insulin-sensitizing response to rosiglitazone
treatment, but don’t show reduced bone density, or increased fluid retention and heart rate. Further, in
collaboration with Drs. Tabas and Tall, they show that atherosclerosis plaque formation is reduced in 2KR mice
overexpressing PCSK9, and efferocytosis greatly increased in 2KR macrophages compared to WT. The PIs
hypothesize that, when transferred on the Ldlr–/– background, the 2KR mutant PPARg will (a) decrease
plaque formation, (b) reduce the adverse effects of TZD treatment on bone loss, cardiac hypertrophy, and fluid
balance, and (c) promote atherosclerosis regression in animals with established lesions treated with TZD. To
test the hypothesis, they will: in Aim 1 study the effect of the 2KR mutation on atherosclerosis progression and
regression using crosses with Ldl receptor knockout mice (Ldlr–/–), followed by bone marrow transplants to
determine the main site(s) of the expected protective effect. They will also examine whether 2KR-Ldlr–/– mice are
protected from rosiglitazone’s adverse effects. In Aim 2 they will study the effect of 2KR in macrophage function,
with a focus on efferocytosis (Tabas collaboration) and cholesterol efflux (Tall collaboration); in Aim 3 they will
seek to identify the critical mediators of 2KR action by an integrative approach combining gene expression with
genome-wide histone modification and enhancer studies in macrophages.

## Key facts

- **NIH application ID:** 10197191
- **Project number:** 5P01HL087123-14
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** DOMENICO ACCILI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $546,810
- **Award type:** 5
- **Project period:** 2007-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197191

## Citation

> US National Institutes of Health, RePORTER application 10197191, PPAR-gamma Deacetylation in Cardiometabolic Disease (5P01HL087123-14). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197191. Licensed CC0.

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