# Biological Mechanisms through which TMAO Promotes Atherosclerosis

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $601,080

## Abstract

PROJECT SUMMARY
 Cardiovascular disease (CVD) remains the leading cause of death in the US but traditional risk factors,
such as elevated lipid levels and hypertension, account for less than 50% of the risk for CVD. We have
recently identified a novel mechanism for atherosclerosis where trimethylamine N-oxide (TMAO), a metabolite
derived from gut microbiome and hepatic-mediated metabolism of dietary choline and L-carnitine, increases
aortic lesion formation in mice and is associated with elevated risk of CVD in humans. Our data further
indicate that TMAO levels are regulated through complex interactions between dietary substrates and host
genetic factors in the liver and other organ systems. However, the biological pathways that regulate TMAO at
the level of hepatic production and whether these factors interact with dietary choline or L-carnitine to affect
atherosclerosis are not known. Furthermore, many questions remain unanswered with respect to the biological
mechanisms by which TMAO promotes atherogenesis and whether the association between TMAO and CVD
in humans represents a causal relationship. The integrative strategies proposed herein directly address these
critical gaps in knowledge. In Specific Aim 1, we will determine the biological mechanisms underlying the pro-
atherogenic properties of TMAO using a genetically modified mouse model that we recently created for
deficiency of flavin-containing monooxygenase 3 (Fmo3), the major enzyme responsible for hepatic TMAO
production. Fmo3 null mice will be comprehensively characterized for aortic lesion development in the context
of a atherogenic high choline diet. We will also use pharmacological and genetic perturbations strategies in
mouse models to determine in vivo whether the inflammatory processes TMAO promotes at the level of the
vessel wall are mediated through the NF-B pathway. In Specific Aim 2, we will use comparative systems
genetics strategies with >41,000 subjects and a panel of ~100 inbred mouse strains to identify genetic factors
influencing plasma TMAO levels through main effects and/or gene-dietary interactions. The results of these
synteny mapping studies will be used for in silico and Mendelian randomization analyses in >500,000 subjects
to establish a causal relationship between TMAO and risk of CVD. In combination, the proposed studies have
the potential to 1) elucidate the inflammatory mechanisms through which TMAO promotes atherosclerosis; 2)
identify the genetic determinants of a novel and clinically important risk factor for CVD as well as provide a
better understanding of how interactions between genes and dietary factors mediate changes in plasma TMAO
levels and CVD risk; and 3) provide genetic evidence that the relationship between TMAO and CVD is causal.
Taken together, results from our studies would support the notion that targeting TMAO is a novel therapeutic
strategy that may decrease CVD risk independent of known biological pathways and risk factors.

## Key facts

- **NIH application ID:** 10592245
- **Project number:** 5R01HL148110-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Hooman Allayee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $601,080
- **Award type:** 5
- **Project period:** 2020-04-20 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10592245

## Citation

> US National Institutes of Health, RePORTER application 10592245, Biological Mechanisms through which TMAO Promotes Atherosclerosis (5R01HL148110-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10592245. Licensed CC0.

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