# Epigenetic Mechanisms in Developmental Programming of Hepatic Lipid Dysfunction by Maternal Hypercholesterolemia

> **NIH NIH R03** · STATE UNIVERSITY OF NEW YORK AT BUFFALO · 2024 · $161,000

## Abstract

Project Summary/Abstract: Maternal hypercholesterolemia (MHC) is a pathological condition of exaggerated
maternal serum cholesterol during gestation. Although there is a normal rise in maternal cholesterol during
pregnancy which is vital for early organ development, an excessive increase can manifest in women with
elevated cholesterol prior to conception. Further, pregnancy conditions such as maternal obesity, gestational
diabetes, and preeclampsia are associated with overt hypercholesterolemia.
 MHC is associated with adverse pregnancy outcomes (i.e., pre-term delivery and low birth weight) and
a range of metabolic complications in offspring including increased adiposity, fetal fatty streaks that develop
faster in childhood, and the programming of non-alcoholic fatty liver disease (NAFLD). Alarmingly, as the use
of lipid-lowering medication in MHC is contraindicated due to fears around fetal toxicity, there are limited
acceptable treatment options and an acknowledged increase in disease risk for offspring from hyper-
cholesterolemic mothers before they are even born.
 This proposal addresses two critical knowledge gaps for MHC: (i) the scarcity of information on how
excessive early cholesterol exposure impacts the offspring’s hepatic epigenome and how these modifications
may influence NAFLD progression; and (ii) an alarming lack of cholesterol-lowering treatment options for use
during MHC. As safe and effective plant-based cholesterol-lowering agents, phytosterols (PS) and their
saturated derivatives, phytostanols (PSA) are highly suitable candidates.
 Using a diet-induced hypercholesterolemic C57BL/6J mouse model, this proposal seeks to identify the
hepatic epigenomic adaptations to excessive early-life cholesterol exposure and the influence of
maternal cholesterol-lowering strategies on the molecular and metabolic features of NAFLD in
offspring. Employing methylated DNA immunoprecipitation sequencing, these studies will examine how MHC
throughout pregnancy alters the DNA methylation pattern of hepatic lipid-regulatory genes in early life and
determine the persistence of these molecular adaptations into adulthood. Further, we will directly compare the
efficacy of maternal PS versus PSA intervention as strategies to limit fetal exposure to excessive cholesterol
and protect against the programming of NAFLD in offspring.
 This proposal addresses the critical question of how to make pregnancies safer for
hypercholesterolemic mothers and their children. The novel ideas presented in this proposal directly reflect the
research priorities of the National Institute of Child Health and Human Development (NICHD) with particular
respect to the Pediatric Growth and Nutrition Branch that seeks to ‘understand the mechanisms of growth
and development at the gene-molecular level’ and ‘identify the molecular drivers that transmit the memory of
adverse intrauterine environments into adolescence and adulthood’.

## Key facts

- **NIH application ID:** 10808606
- **Project number:** 1R03HD104742-01A1
- **Recipient organization:** STATE UNIVERSITY OF NEW YORK AT BUFFALO
- **Principal Investigator:** Michael Joseph Buck
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $161,000
- **Award type:** 1
- **Project period:** 2024-07-23 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808606

## Citation

> US National Institutes of Health, RePORTER application 10808606, Epigenetic Mechanisms in Developmental Programming of Hepatic Lipid Dysfunction by Maternal Hypercholesterolemia (1R03HD104742-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10808606. Licensed CC0.

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