# Mechanisms underlying hepatic immune cell recruitment in nonalcoholic fatty liver disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2022 · $421,886

## Abstract

PROJECT SUMMARY/ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is a spectrum of progressive conditions ranging from nonalcoholic fatty
liver (NAFL) or hepatic steatosis to the more severe nonalcoholic steatohepatitis (NASH) characterized by
excessive inflammation and varying degrees of fibrosis. NASH-related cirrhosis is the second leading cause of
liver transplantation in the United States and NASH patients face an increased risk of developing hepatocellular
carcinoma. The incidence of NASH and NASH-related cirrhosis continues to rise; there, are no FDA-approved
therapies as we lack a clear understanding of the cellular and molecular mechanisms driving the progression of
NAFL to NASH and the subsequent development of cirrhosis. While there is mounting evidence that inflammation
is central to the initiation and progression of NAFLD, the specific immune pathways that drive inflammation in
this setting are not well understood. The objective of this proposal is to improve our functional understanding of
the mechanisms by which immune cells contribute to NASH-related hepatic inflammation, and to identify the key
molecules underlying recruitment of immune cells to the liver. Our published findings and preliminary data have
demonstrated that the heterodimeric integrin receptor α4β7 and its ligand, mucosal addressin cell adhesion
molecule-1 (MAdCAM-1), play a pivotal role in NASH-related hepatic inflammation and fibrosis by promoting the
recruitment of inflammatory monocytes and CD4 T cells to the liver. These data provide the scientific rationale
for our central hypothesis that the α4β7/MAdCAM-1 axis drives hepatic inflammation and fibrosis in NASH by
promoting recruitment of proinflammatory monocytes and CD4 T cells to the liver. We will test this hypothesis in
both a mouse model of progressive NAFLD and in human liver tissue from NASH patients according to the
following integrated Specific Aims. Aim 1 will investigate the contribution of α4β7+ monocytes and CD4 T cells in
promoting hepatic inflammation in NASH. Aim 2 focuses on the role of hepatic stellate cells in the regulation of
immune cell recruitment to the NASH liver. Lastly, Aim 3 investigates the mechanisms regulating the
α4β7/MAdCAM-1 axis in NASH. The results of our investigations will provide comprehensive and mechanistic
insights into the inflammatory events crucial to the pathogenesis of NASH, and may lead to the identification of
viable therapeutic targets for regulating hepatic inflammation. Given the importance of immune cells in governing
metabolic inflammation and the therapeutic potential of targeting immune cells, this proposal addresses
significant and clinically relevant issues in NASH.

## Key facts

- **NIH application ID:** 10372225
- **Project number:** 5R01DK124351-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Reben Raeman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $421,886
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372225

## Citation

> US National Institutes of Health, RePORTER application 10372225, Mechanisms underlying hepatic immune cell recruitment in nonalcoholic fatty liver disease (5R01DK124351-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10372225. Licensed CC0.

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