# Understanding Mechanisms that Regulate Liver Growth and Function

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2024 · $478,285

## Abstract

Project Abstract
Chronic liver diseases are on the rise and are associated with almost $100 billion in healthcare
costs in the United States. Since the liver is a primary site for detoxification and metabolizes a
variety of chemicals, prescription drugs, and nutrients, it is prone to constant damage. To cope
with the insults, the liver has inherent mechanisms, including division of labor, polyploidy, and
injury-associated liver regeneration.
Although liver metabolism and liver diseases exhibit sexual dimorphism, studies focused on
understanding sex differences in liver injury and regeneration are lacking. The nuclear receptor,
Constitutive Androstane receptor (CAR), controls detoxification, and several metabolic pathways
and is linked to liver growth. But spatiotemporal and sex-specific CAR-mediated regulation
remains unexplored. We still do not know if and how CAR (i) regulates zonation and if CAR
targets distinct genes in the different zones of the liver, (ii) controls polyploidy and injury-
associated regeneration, (iii) influences estrogen receptor α (ERα)-mediated signaling, and (iv)
contributes to the sex differences seen in liver metabolism and functions. This study is designed
to address these gaps.
In this renewal, we combine high throughput analysis of transcriptomes and cistromes using a
novel epitope-tagged FLAG-CAR mouse and different chemical-based liver injury models to
decipher how CAR orchestrates various aspects of hepatic metabolism and functions. In specific
aim 1, we will determine if CAR is necessary for metabolic maturation and maintaining
heterogeneity of hepatocytes, whereas in specific aim 2, we will determine the role of the CAR-
ERα axis in regulating sex differences in polyploidy and regeneration in the liver.
The long-term objective of these studies is to gain comprehensive understanding of the molecular
mechanisms that integrate metabolic functions and liver regeneration and growth. Our proposed
studies will uncover new insights and elaborate on a fundamental aspect of CAR in controlling the
metabolic fitness of hepatocytes. This knowledge, in turn, can be maneuvered to prevent and or
treat liver diseases.

## Key facts

- **NIH application ID:** 10981706
- **Project number:** 2R01DK113080-06A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Sayeepriyadarshini Anakk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $478,285
- **Award type:** 2
- **Project period:** 2017-07-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981706

## Citation

> US National Institutes of Health, RePORTER application 10981706, Understanding Mechanisms that Regulate Liver Growth and Function (2R01DK113080-06A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10981706. Licensed CC0.

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