# Autocrine/Paracrine Regulation of Intrahepatic Bile Duct Growth

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2020 · —

## Abstract

Nonalcoholic fatty liver disease (NAFLD) is an alarming public health concern and now considered the most
common liver disease in the Western world. Patients with NAFLD may develop nonalcoholic steatohepatitis
(NASH) of which many develop hepatic injury that may progress to cirrhosis. We have previously shown
that in chronic cholestatic liver diseases, cholangiocytes, through the products of their cellular activation
such as secretin (SCT), are the key link between bile duct injury and the subepithelial fibrosis that
characterizes chronic hepatobiliary injury. We have also demonstrated that activation of the SCT/SR axis
plays a key role in the progression of liver fibrosis and biliary damage during cholestasis in animal models
and human liver samples via secretion of transforming growth factor-b1 (TGF-b1) by cholangiocytes and
subsequent activation of hepatic stellate cells (HSCs). Recent evidence and our novel preliminary data
indicate that cholangiocytes play a key role in the pathogenesis of NAFLD/NASH through activation of
biliary damage/proliferation and subsequent liver fibrosis. Our preliminary data that the SCT/secretin
receptor (SR) axis is upregulated in cholangiocytes in an animal model of NAFLD/NASH and human liver
samples with steatosis and steatohepatitis support the concept that the SCT/SR axis plays a key role in the
progression of NAFLD and NASH. Based upon these findings, we propose the central hypothesis that the
SCT/SR axis signaling is key for mediating the proliferative and activated profibrogenic biliary phenotype
that contributes to the progression of hepatic steatosis and fibrosis during the pathogenesis of
NAFLD/NASH. To test our hypothesis, two Specific Aims are proposed: (i) activation of the SCT/SR axis
stimulates a neuroendocrine/profibrogenic biliary phenotype in response to FFA-induced biliary damage
triggering the activation of HSCs via a paracrine TGF-b1-dependent mechanism; and (ii) inhibition of the
SCT/SR axis and downstream pathways attenuates the activated neuroendocrine/profibrogenic biliary
phenotype and hepatic steatosis and fibrosis during the progression of NAFLD/NASH. Completion of the
proposed studies will provide a translational mechanism of how activation of the SCT/SR axis promotes
local and systemic responses to mediate activation of neuroendocrine/profibrogenic biliary phenotype and
hepatobiliary steatosis and fibrosis during the progression of NAFLD/NASH.!

## Key facts

- **NIH application ID:** 9896734
- **Project number:** 5I01BX000574-11
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Gianfranco D Alpini
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-10-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896734

## Citation

> US National Institutes of Health, RePORTER application 9896734, Autocrine/Paracrine Regulation of Intrahepatic Bile Duct Growth (5I01BX000574-11). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896734. Licensed CC0.

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