# APOB48 downregulation is the causing factor in mediating iAs-induced lipid accumulation in enterocytes

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $434,500

## Abstract

ABSTRACT
Early life exposure to arsenic during fetal and neonatal development is a prerequisite to accelerated toxicity
and delayed health consequences. Humans ingest arsenic through contaminated drinking water and foods
with the intestinal tract being the primary site for arsenic absorption. With whole life exposure to arsenic
occurring worldwide, there is limited data available on arsenic’s effects on the intestinal tract, especially during
the early developmental stage. Our laboratory has demonstrated that oral arsenic treatment induces
oxidative stress in the intestinal tissues, altering significant overall gene expression. Most recently, we
observed that oral administration of inorganic arsenic (iAs) to neonatal mice dramatically accelerates
intestinal stem cell (ISC) proliferation and intestinal epithelial cell (IEC) differentiation. Histological
examination and biochemical analysis have revealed that iAs exposure leads to drastic lipid accumulation in
intestinal enterocytes. When we treated neonatal mice with oleic acid, which is abundant in breast milk, this
treatment mimics what we observed with iAs-induced pathophysiological changes in the small intestine. Thus,
it is likely that lipid accumulation from iAs exposure mediates iAs-induced intestinal effects. As the functionality
of the digestive tract is determined primarily by the small intestine, through altering the epithelium function,
early life iAs exposure may generate a myriad of health challenges that could predispose individuals to a
greater disease vulnerability. Therefore, understanding how iAs impacts on intestinal lipid metabolism will
be the focus of our studies. We have identified that apolipoprotein B48 (APOB48), the structural
component of chylomicron synthesis and secretion, is dramatically downregulated following iAs exposure. We
will test the hypothesis that downregulated APOB48 is the causing factor in mediating iAs-induced lipid
accumulation in enterocytes. In this proposal, we will determine the functional outcomes of APOB48
downregulation by measuring lipid content in plasma samples, including lipid profiling, levels of fat-soluble
vitamins, and essential fatty acids. We will determine the fat absorption capability in mice following iAs
exposure (Aim 1). We will also determine if overexpression of the constitutive active APOB48 in intestinal
tissue counters iAs induced enterocyte lipid accumulation by conducting experiments in transgenic mice
carrying a villin-promoter driven human APOB cDNA (Aim 2). We contend that these experiments will
lay the foundation for an understanding of the underlying mechanisms leading to iAs induced intestinal lipid
accumulation in neonatal mice, an event that we predict may predispose mice to accelerated physiological
changes and diseases later in life.

## Key facts

- **NIH application ID:** 10538854
- **Project number:** 1R21ES034630-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Robert H Tukey
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $434,500
- **Award type:** 1
- **Project period:** 2022-09-16 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10538854

## Citation

> US National Institutes of Health, RePORTER application 10538854, APOB48 downregulation is the causing factor in mediating iAs-induced lipid accumulation in enterocytes (1R21ES034630-01). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10538854. Licensed CC0.

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