# Mechanisms of AHR Metabolic Toxicity

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $424,575

## Abstract

ABSTRACT
 This research will address a major knowledge gap in aryl hydrocarbon receptor (AHR) biology: how
transcriptional activation of the AHR by the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin,
TCDD) causes metabolic toxicities including suppressed glucose production, energy failure and hepatic
steatosis. We will investigate the role of NAD+ depletion in AHR metabolic toxicities. NAD+ is a small molecule
important in cellular redox reactions and is a required substrate for the catalytic activity of PARPs and sirtuins,
enzymes that regulate energy metabolism, genome stability and aging. This research will provide new
understanding of the basis of AHR metabolic toxicities by probing our finding that TCDD decreases NAD+
levels through the AHR target gene TiPARP (TCDD-inducible poly ADP-ribosylase, PARP7), one of the PARP
enzymes which consume NAD+ while ADP-ribosylating proteins. We will exploit here our discoveries that
TiPARP contributes to decreased hepatic glucose production by consuming NAD+ and suppressing induction
by sirtuin 1 of PEPCK, a rate limiting enzyme in gluconeogenesis. Longer exposure to TCDD also increases
hepatic PARP1 levels suggesting that PARP1 may contribute to lowering NAD+ levels. We propose two
connected Specific Aims (SA): SA1 will study the consequences of NAD+ depletion on sirtuin activity and
mitochondrial bioenergetics, will establish the role of TiPARP and PARP1 in TCDD toxicities in mammalian
model and will seek to identify NAD-repletion as a preventive and corrective strategy against TCDD toxicity.
SA2 will examine the role of ADP-ribosylation by TiPARP in AHR action. Specifically, these studies will
elucidate the consequences of NAD+ depletion for biological and catalytic activities of Sirts1, 3 and 6, using
new sirtuin specific assays (SA1a1). A role of NAD+ depletion by TCDD in mitochondrial bioenergetics will be
addressed by studies using Seahorse technology to examine oxygen consumption and glycolysis (SA1a2).
Chick embryo hepatocytes will be used throughout the grant, and we will confirm major findings in human
primary hepatocytes. Liver-specific TiPARP and PARP1 KO mice will be used to assess their roles in the
production of TCDD metabolic toxicities in a mammalian model (SA1b). SA1c will determine whether NAD+
repletion with nicotinamide, and other NAD+ repleting agents, can prevent and possibly correct TCDD
toxicities. SA2 will examine the role of ADP-ribosylation by TiPARP in AHR metabolic toxicities as we found
that PEPCK is ADP-ribosylated by TiPARP. We will examine (SA2a) the effects of ADP-ribosylation of PEPCK
by TiPARP on PEPCK stability and activity and will seek to identify other proteins ADP-ribosylated by TiPARP
to reveal new ways by which ADP-ribosylation could participate in AHR action (SA2b). We expect this research
to establish a significant mechanism in which NAD+ depletion by PARP activity leads to TCDD hepatic
metabolic toxicities and to identify NAD+-repletion as a...

## Key facts

- **NIH application ID:** 10112906
- **Project number:** 5R01ES027488-05
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Yue Yang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $424,575
- **Award type:** 5
- **Project period:** 2017-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10112906

## Citation

> US National Institutes of Health, RePORTER application 10112906, Mechanisms of AHR Metabolic Toxicity (5R01ES027488-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10112906. Licensed CC0.

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