# Role of Sensory Innervation in High Fat Diet-Induced Hepatotoxicity

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $567,143

## Abstract

Project Summary
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 may develop hepatic injury that may progress to liver cirrhosis. We have shown that activation
of the alpha-calcitonin gene-related peptide (CGRP)/Calcitonin receptor-like receptor (CRLR) axis plays a key
role in cholangiocyte proliferation induced by biliary damage during cholestasis in animal models. 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, ductular reaction (DR), senescence, and subsequent liver
fibrosis. Our preliminary data showing that the CGRP/CRLR axis is upregulated in cholangiocytes in animal
models of NAFLD/NASH (high-fat diet (HFD) and methionine and choline-deficient (MCD) hepatoxic diet) and
human liver samples with NAFLD and NASH support the concept that the CGRP/CRLR axis plays a key role
in the progression of NAFLD and NASH phenotypes. Based upon these findings, we propose the central
hypothesis that the CGRP/CRLR axis signaling is critical for mediating DR and activated profibrogenic biliary
phenotype that triggers HSC activation, as well as steatosis in hepatocytes contributing to the progression of
hepatic fibrosis during NAFLD/NASH. To test our hypothesis, two Specific Aims are proposed: (i) HFD and MCD
hepatoxic diet-induced activation of the CGRP/CRLR axis stimulates DR, biliary senescence triggering the
subsequent steatosis and fibrosis during NAFLD/NASH; and (ii) Therapeutic inhibition of the CGRP/CRLR axis
and downstream pathways attenuates the activated neuroendocrine/profibrogenic biliary phenotype hepatic
steatosis and fibrosis during the progression of NAFLD/NASH. The proposed studies will be performed in cell
specific CRLR knockout mice models as well as in vitro studies in human NAFLD/NASH cholangiocytes cell lines
and 3D organoids. The activation of the CGRP/CRLR axis and downstream pathways will be correlated in human
samples of NAFLD/NASH. Successful completion of the proposed studies will provide a translational mechanism
of how activation of the CGRP/CLR axis mediates DR and hepatobiliary fibrosis during the progression of
NAFLD/NASH. Our study will also provide insight for novel therapeutic approaches for NAFLD/NASH and other
liver diseases characterized by ductular reaction and hepatobiliary fibrosis.

## Key facts

- **NIH application ID:** 10467095
- **Project number:** 1R01DK132891-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Gianfranco D Alpini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $567,143
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467095

## Citation

> US National Institutes of Health, RePORTER application 10467095, Role of Sensory Innervation in High Fat Diet-Induced Hepatotoxicity (1R01DK132891-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10467095. Licensed CC0.

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