# Xenobiotic-responsive hepatic long non-coding RNAs

> **NIH NIH R01** · BOSTON UNIVERSITY (CHARLES RIVER CAMPUS) · 2021 · $471,971

## Abstract

7. Project Summary/Abstract
Many industrial chemicals, environmental pollutants and other xenochemicals activate transcription factors
belonging to the nuclear receptor superfamily, which leads to widespread genomic, epigenetic and
transcriptional changes that disrupt key biological pathways and metabolic processes in liver and other
tissues. The studies proposed focus on the liver nuclear receptor CAR (Constitutive Androstane Receptor;
NR1I3), which is activated by structurally diverse xenochemicals and regulates transcription of hundreds of
protein-coding genes important for processes such as xenobiotic metabolism, lipogenesis, glucose
homeostasis, and inflammation, and has been implicated as a regulator of non-alcoholic fatty liver disease
(NAFLD) development. We have discovered that xenobiotic agonists of CAR and other xenobiotic-responsive
receptors induce or repress the transcription of several hundred nuclear-enriched long non-coding RNAs
(lncRNAs) with epigenetic and gene regulatory potential, many of which have human orthologs. This proposal
builds on these findings and on recent advances in liver cell zonation, single cell-based transcriptomic
profiling, and gene co-expression network analysis to elucidate in an intact mouse liver model the effects of
CAR-responsive lncRNAs on fatty liver disease induced by foreign chemical exposure. The studies proposed
test the hypothesis that a subset of CAR-responsive lncRNAs control hepatic gene regulatory networks driving
NAFLD and downstream pathologies, dysregulating processes such as lipid and carbohydrate metabolism,
hepatic architecture and mitochondrial function in a liver cell type-specific and hepatic lobule zone-dependent
manner. The work proposed uses TCPOBOP (1,4-bis[2-(3,5-dichloro-pyridyloxy)]benzene), a prototypic non-
genotoxic chemical and CAR-specific agonist ligand, to address the seemingly paradoxical finding that
persistent exposure to foreign chemical CAR activators induces NAFLD in mice fed normal chow diet, but
suppresses NAFLD development in mice fed a high fat diet. These studies will elucidate the role of CAR, and
the lncRNAs that it regulates, in fatty liver disease etiology and progression. Results obtained will give critical
insight into the underlying mechanisms by which foreign chemicals dysregulate CAR-dependent metabolic
pathways linked to NAFLD, which affects 25% of US adults and is a major cause of cirrhosis, hepatocellular
cancer and liver failure. This work will refocus research efforts on xenochemical action to include mechanistic
studies of single cell-based, spatially zonated gene regulatory networks and the non-coding transcriptome,
and will serve as a paradigm for other foreign chemical-activated receptors that dysregulate gene expression
in complex ways. Together, the proposed studies on CAR-responsive lncRNAs and their role in xenochemical-
induced liver pathology may lead to new ways to prevent, diagnose or treat liver diseases induced by chemical
expos...

## Key facts

- **NIH application ID:** 10210396
- **Project number:** 5R01ES024421-07
- **Recipient organization:** BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
- **Principal Investigator:** DAVID J WAXMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $471,971
- **Award type:** 5
- **Project period:** 2014-08-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210396

## Citation

> US National Institutes of Health, RePORTER application 10210396, Xenobiotic-responsive hepatic long non-coding RNAs (5R01ES024421-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10210396. Licensed CC0.

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