# Dysregulation of hypothalamic neuropeptides is associated with biliary hyperplasia

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $354,874

## Abstract

Project Summary/Abstract  
 
Cholangiocytes are the target cells in cholestatic liver diseases such as primary biliary cirrhosis (PBC) and
primary sclerosing cholangitis (PSC). During the course of these diseases, mitotically dormant cholangiocytes
are stimulated to proliferate and then undergo ductopenia. Associated with these cholangiopathies is a
dysregulation of various neuroendocrine factors derived from the hypothalamus and the acquisition of a
neuroendocrine phenotype in cholangiocytes. Taken together, these events contribute to the autocrine and
paracrine pathways that modulate the proliferative response of cholangiocytes as well as liver damage and
fibrosis in cholestatic liver injury. We have previously shown that circulating neuropeptide Y (NPY) and
corticoptropin releasing hormone (CRH) are altered in models of biliary proliferation. Furthermore, we have
recently demonstrated that the hypothalamic-pituitary-adrenal axis (HPA) is dampened during extrahepatic
biliary obstruction resulting in suppressed glucocorticoid levels. Reactivation of the HPA axis by hypothalamic
administration of CRH suppresses the proliferative capacity of cholangiocytes after bile duct ligation (BDL),
suggesting a broader concept of hypothalamic control over cholangiocyte proliferation. The objective of this
proposal is to investigate mechanisms by which extrahepatic biliary obstruction regulates the peripheral and
central expression and activity of orexigenic peptides, and the subsequent effects on cholangiocyte
proliferation. Based upon strong preliminary data, we propose the novel central hypothesis that early release of
bile acids into the serum as a result of cholestasis results in the suppression of ghrelin expression from the
stomach and increased production of leptin from adipose tissue. This imbalance results in the subsequent
suppression of NPY and increase in αmelanocyte stimulating hormone (αMSH) expression in the
hypothalamus, both of which are exacerbated by hypothalamic bile acid signaling. These peripheral and
central changes in neuropeptide expression co-ordinately regulate cholangiocyte proliferation and biliary
fibrosis. Our proposed work will focus on two specific aims that have been designed to test the following
working hypotheses: 1) The imbalance between ghrelin and leptin during cholestasis is a result of aberrant bile
acid signaling in the periphery and contributes to the resulting liver pathology; and 2) Hypothalamic NPY and
αMSH are altered as a consequence of co-ordinate bile acid signaling in the hypothalamus and alterations in
the peripheral ghrelin/leptin balance. Dissecting the pathophysiological interactions between the brain and the
liver during cholestatic liver diseases may lead to an enhanced understanding of the pathological processes
and consequences of this particular type of liver disease. This knowledge may play a paramount role in the
development of therapeutic strategies for the treatment of cholangiopathies.

## Key facts

- **NIH application ID:** 9987619
- **Project number:** 5R01DK082435-10
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Sharon DeMorrow
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $354,874
- **Award type:** 5
- **Project period:** 2010-07-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987619

## Citation

> US National Institutes of Health, RePORTER application 9987619, Dysregulation of hypothalamic neuropeptides is associated with biliary hyperplasia (5R01DK082435-10). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9987619. Licensed CC0.

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