# The Impact of Maternal Western Style Diet on Immune Cell Function and Development of Non-Alcoholic Fatty Liver Disease

> **NIH NIH F30** · UNIVERSITY OF COLORADO DENVER · 2021 · $32,973

## Abstract

Abstract/Project Summary
Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease worldwide. However,
its pathophysiology is unresolved and treatment options are lacking. Poor maternal diet and obesity promote
NAFLD in offspring, but the mechanisms by which this occurs are not clear. We propose to identify the impact
of maternal western style diet (WSD) on offspring immune cell and liver phenotypes in a non-human primate
(NHP) model with features similar to human pediatric NAFLD. While the pathophysiology of NAFLD is
multifactorial, pro-inflammatory macrophage (Mφ) activation and recruitment of bone marrow monocytes to the
liver are critical for its progression. The innate immune system is derived from hematopoietic stem cells (HSCs),
which reside primarily in the bone marrow. Maternal diet has been shown to skew HSC function, which may
manifest as alterations in Mφ development and activity, potentially promoting NAFLD progression. We find that
maternal WSD in our NHP model increases fetal steatosis (liver fat), decreases proliferation of bone marrow
cells and causes a proportional increase in myeloid (innate immune) cell production. Strikingly, these phenotypes
are also present in juvenile NHP exposed to maternal WSD then weaned onto a healthy diet for the remainder
of life. In addition, we observe dysregulated Mφ cytokine response in NHP fetuses exposed to maternal WSD.
Finally, hypoxia-inducible factor (HIF)-1a has emerged as a critical driver of the Mφ pro-inflammatory phenotype.
Our preliminary data in mice show that mice fed a WSD have increased hepatic Mφ HIF1A RNA expression and
HIF-1a protein stabilization has been shown to promote Mφ inflammation and fibrosis in mice. This suggests
that inhibiting HIF1a in bone marrow may prevent inflammatory Mφ activity in NAFLD. Therefore, current data
supports the novel hypothesis that maternal WSD differentially programs HSCs in utero to promote
persistent myeloid cell skewing and downstream Mφ dysfunction that ultimately drives liver damage and
fibrosis later in life, and that Hif1a is necessary for this Mφ dysfunction. To investigate this hypothesis we
propose to: 1) We will utilize qPCR and microscopic techniques in livers from fetal and juvenile NHPs to
determine the impact of maternal WSD on fibrosis, tissue inflammation and lipid content. We will also investigate
the transcriptional phenotypes and proportions of recruited vs. resident Mφ in livers, to determine the relative
contributions of these cells in promoting NAFLD. 2) Identify how maternal WSD alters transcriptional pathways
in HSCs responsible for shifts in HSC development, proliferation, and Mφ phenotypes in NHP offspring, including
Mφ cytokine response. 3) We will test whether deletion of Hif1a in hematopoietic cells in mice is necessary for
maternal WSD induced alterations in pro-inflammatory hepatic Mφ response and fibrosis. These studies will give
descriptive and mechanistic insight into how maternal ...

## Key facts

- **NIH application ID:** 10242778
- **Project number:** 5F30DK122672-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Michael J Nash
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $32,973
- **Award type:** 5
- **Project period:** 2019-09-13 → 2023-09-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10242778

## Citation

> US National Institutes of Health, RePORTER application 10242778, The Impact of Maternal Western Style Diet on Immune Cell Function and Development of Non-Alcoholic Fatty Liver Disease (5F30DK122672-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10242778. Licensed CC0.

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