# A Cardiovascular-NASH disease nexus: Common Mechanisms and Treatments?

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $2,537,053

## Abstract

PROJECT SUMMARY
Overall
Despite the development of increasingly effective therapies to reduce elevated levels of atherogenic lipoproteins,
cardiovascular disease (CVD) complications are projected to rise worldwide due in part to the increasing
incidence of obesity and insulin resistance. An emergent question is the extent to which non-alcoholic fatty liver
disease (NAFLD), which is a spectrum ranging from fatty liver to non-alcoholic steatohepatitis (NASH) to cirrhosis,
contributes to CVD risk. Among patients with NAFLD, the leading cause of death is CVD, estimated to account
for 31% of total mortality. The development of NAFLD and cardiovascular disease is influenced by combinations
of genetic and environmental factors, some of which are disease-specific and others that affect both disease
processes. The overall hypotheses of our PPG are that liver fat and fibrosis predict CVD risk and that
interventions targeting Liver X receptors (LXRs) in macrophages, the farnesyl X receptor (FXR) in the gut, and
oxidation specific epitopes (OSEs) in the liver and artery wall will reveal common mechanisms that contribute to
the clinical association between NASH and CVD. Importantly, each of these interventions make use of
representative small molecules or antibodies that have the potential to be advanced for clinical trials. Identifying
mechanisms by which known and unknown risk factors promote both NASH and CVD would be of great
significance, especially if targeting one or more of these mechanisms would produce beneficial effects on both
diseases. To achieve this goal, we propose a PPG consisting of four highly inter-related projects and three cores.
Project 1, led by Dr. Christopher Glass, will test the hypothesis that selective activation of LXRs in macrophages
and Kupffer cells with desmosterol mimetics will result in reductions of atherosclerosis and NASH without causing
steatosis or hypertriglyceridemia. Project 2, led by Dr. Ronald Evans, will investigate the hypothesis that
selective activation of FXR in the gut or liver will result in reductions in atherosclerosis and NASH. Project 3,
led by Dr. Joseph Witztum, will test the hypothesis that antibody-mediated reductions in OSEs will coordinately
reduce both atherosclerosis and NASH. Project 4, led by Dr. Rohit Loomba, will investigate the relationships of
liver fat content and fibrosis with cardiovascular risk in human subjects and enable translational extension of
mechanistic findings made in Projects 1, 2 and 3. A Phenotyping Core will enable Projects 1, 2 and 3 to
quantitatively evaluate extent of atherosclerosis and NASH in mouse models, and enable all projects to obtain
targeted lipidomic profiles and cytokine levels from relevant samples. A Genomics and Bioinformatics Core
will support the application of massively parallel sequencing-based assays, such as RNA Seq, by Projects 1, 2
and 3 and provide a shared resource for bioinformatics and statistical analysis. An Administrative Core will
support...

## Key facts

- **NIH application ID:** 9936770
- **Project number:** 1P01HL147835-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Christopher K Glass
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $2,537,053
- **Award type:** 1
- **Project period:** 2020-09-21 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936770

## Citation

> US National Institutes of Health, RePORTER application 9936770, A Cardiovascular-NASH disease nexus: Common Mechanisms and Treatments? (1P01HL147835-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9936770. Licensed CC0.

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