# Mechanisms of Atherogenesis in Insulin Resistance

> **NIH NIH P01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $2,130,062

## Abstract

The marked increase in cardiovascular disease in patients with type 2 diabetes (T2D) demands an
integrated cardiometabolic approach. Using this approach, the PPG team has had a highly interactive and
productive collaboration for the last 10 years and plans to move forward to explore common
transcriptional and signaling mechanisms in distinct cell types that contribute to cardiometabolic
disease. This goal will be achieved through continued synergistic interactions among the 3 projects and
Core A. Project 1 (Tabas) will explore how a common upstream CaMKII/MK2 pathway in hepatocytes
(HCs) and macrophages (Ms) promotes insulin resistance and plaque progression, respectively—and how
the HC pathway amplifies the M pathway through systemic insulin resistance. The project has a
mechanism-based therapeutic/translational component and involves key collaborations with Drs. Tall and
Accili. For example, Drs. Tabas & Tall will explore the novel finding that the M CaMKII/MK2 pathway down-
regulates LXR, thereby impairing a key atheroprotective process, efferocytosis. Project 2 (Tall) will explore
the role of T39 in HCs, lesional Ms, and adipocytes. In HCs and Ms, T39 alters LXR activation to promote
hepatosteatosis and block the suppressive effect of M LXR on atherosclerosis. Thus, blocking T39
suppresses both atherosclerosis and fatty liver. Drs. Tall & Tabas with study the role of M LXR in
suppressing atherosclerosis in T39-deficient mice (above). In adipocytes T39 suppresses beiging, which
may promote insulin resistance and atherosclerosis. The mechanism involves down-regulation of PPAR1,
which will be explored with Dr. Accili. Project 3 (Accili) addresses a key problem in T2D therapeutics,
namely, thiazolidinedione (TZD) use is markedly limited by cardiogenic fluid retention and bone loss. Dr.
Accili discovered that PPAR, the target of TZDs, can be deacetylated, which alters it function and response
to TZDs. When TZDs are used in insulin-resistant mice expressing deacetylated mutant PPAR ("2KR"),
the insulin-sensitizing benefits remain but fluid retention and bone loss are prevented. With Drs. Tabas &
Tall., Dr. Accili will investigate the relevance of these findings to atherosclerosis and will explore
mechanism. For example, Drs. Accili & Tabas found that Ms from 2KR mice have markedly enhanced
efferocytosis, which predicts decreased plaque progression. 2KR mice also display adipose beiging, and
Drs. Accili & Tall will assess the impact of this on atherogenesis. Core A (Drs. Wang and Wei) will provide
essential support and integration for all of the atherosclerosis studies of the PPG and will also provide
statistical and bioinformatic support to ensure rigor and reproducibility for all projects. In summary, through
synergistic interactions among the PPG PIs, these new studies will reveal important new concepts
and therapeutic targets related to the integrated pathophysiology of cardiometabolic disease.

## Key facts

- **NIH application ID:** 9954131
- **Project number:** 5P01HL087123-13
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Ira A Tabas
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,130,062
- **Award type:** 5
- **Project period:** 2007-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9954131

## Citation

> US National Institutes of Health, RePORTER application 9954131, Mechanisms of Atherogenesis in Insulin Resistance (5P01HL087123-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9954131. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*