# Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $352,529

## Abstract

Non-alcoholic fatty liver disease (NAFLD) develops as a result of fat deposited into the liver (steatosis) caused
by other factors aside from alcohol; and, NAFLD is now the most common liver disease in Western developed
countries. If left untreated or if another insult occurs (“two-hit” hypothesis), NAFLD can develop into NASH.
While hepatocytes are believed to be the primary cell involved in NAFLD, new studies have demonstrated that
both cholangiocytes and mast cells (MCs) contribute to NAFLD progression and potentially to NAFLDèNASH
transition. Further, damaged cholangiocytes undergo senescence and take on a senescence-associated
secretory phenotype (SASP), which may also contribute to the inflammatory environment seen in NASH. MCs
are found in adipose tissue of obese patients and histamine levels are increased in patients with NAFLD,
NASH and end-stage liver disease. To date, no successful treatments have been developed for NAFLD,
aside from altering diet and lifestyle; and, there have been no studies to examine the potential
paracrine interaction between cholangiocytes and MCs in models of NAFLD. Further, the synergistic
relationship between MCs, cholangiocytes, hepatic stellate cells (HSCs) and Kupffer cells has not been fully
examined. The premise of the study is supported by: (i) previous work demonstrating that both cholangiocytes
and MCs contribute to NAFLD; (ii) work from the PI demonstrating that MCs contribute to liver damage and are
critical regulators of disease progression; and, (iii) preliminary data showing that there is a direct interaction
between cholangiocytes and MCs that influences hepatic damage, Kupffer cell activation/inflammation and
HSC-driven fibrosis during NAFLD. In SA1, the PI will examine biliary-induced MC migration using mice
subjected to HFD/HFCS and Vivo-Morpholino treatments to inhibit biliary senescence. This aim will focus
primarily on the interactions between cholangiocytes and MCs. SA2 will focus on the contribution of MCs to
NAFLD progression by using a genetic model of MC depletion and also reintroduction of MCs. These studies
allow us to examine the effects of losing MCs, but also to determine if MCs perpetuate NAFLD progression and
potentially NAFLD to NASH transition (marked by enhanced liver inflammation). Finally, in SA3, the PI will
focus on the inhibition of MC-derived histamine and TGF-b1 using pharmaceutical inhibition to directly target
this inflammatory molecule. Preliminary data and previous publications reveal that TGF-b1 may be a key
modulator of NAFLD and liver damage (including fibrosis); and, MC-derived histamine regulates TGF-b1
expression and secretion. In all of proposed aims, the PI will evaluate NAFLD induced by both Western Diet
(HFD/HFCS) and the methionine-choline deficient (MCD) diet. In addition, features of metabolic syndrome
including insulin resistance, elevated triglycerides, lipoprotein abnormalities, and glucose intolerance will be
evaluated. Targeting MC mediators may b...

## Key facts

- **NIH application ID:** 10170334
- **Project number:** 5R01DK119421-03
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Heather L Francis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,529
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10170334

## Citation

> US National Institutes of Health, RePORTER application 10170334, Mechanisms of mast cell/cholangiocyte regulation of non-alcoholic fatty liver disease progression (5R01DK119421-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10170334. Licensed CC0.

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