# MerTK in NASH-related liver fibrosis

> **NIH NIH R00** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $249,000

## Abstract

Project Summary/Abstract
Nonalcoholic steatohepatitis (NASH) has emerged as the leading cause of chronic liver disease worldwide,
with liver fibrosis being the most important predictor of liver failure in NASH. The lack of definitive mechanisms
of NASH progression, particularly fibrosis limits the design of mechanism-based therapeutic targets and
treatment options. Several independent human GWASs have identified MERTK as a risk factor for liver fibrosis.
However, the mechanisms of MerTK-mediated liver fibrosis are not completely understood. The overall
objective of this proposal is to understand mechanisms of MerTK-induced NASH fibrosis and shed new light on
novel therapeutic strategies to prevent NASH progression. Using a diet rich in fructose, palmitic acid, and
cholesterol (FPC) developed by our group that promotes human-like NASH pathologic features in mice, I found
that genetic targeting of MerTK decreases NASH fibrosis and that MerTK-mediated ERK activation increases
the expression of TGFβ1 in macrophages (Ms), and that MerTK activation increases AKT activity and
collagen gene expression in hepatic stellate cells (HSCs). Moreover, I made an important discovery that
MerTK cell-surface cleavage is decreased in fibrotic livers. Indeed, I found that all-trans retinoic acid (ATRA), a
major active metabolite of retinol found in healthy liver, induces MerTK cleavage in both Ms and HSCs.
Accordingly, I propose that ATRA-induced MerTK cleavage protects against NASH fibrosis but this cleavage is
hampered in fibrotic liver due to the loss of retinoids, leading to the progression of NASH. I propose 3 aims to
study the mechanisms of MerTK-induced NASH fibrosis. Aim1 will explore the hypothesis that MerTK in Ms
contributes to NASH fibrosis. Mertkfl/flLysmCre+/- and the littermate control mice fed the FPC diet will be used to
study the role of M MerTK in NASH fibrosis. I will determine whether M MerTK-induced NASH fibrosis is
through the ERK1/2-AP1-TGFβ1 pathway. Aim2 will investigate the hypothesis that MerTK in HSCs
contributes to NASH fibrosis. Mertkfl/flLratCre+/- mice fed the FPC diet will be used to study the role of HSC
MerTK in NASH fibrosis. I will determine whether HSC MerTK-induced NASH fibrosis is through activating
PI3K/AKT. Aim 3 will explore the hypothesis that suppressing MerTK cleavage promotes NASH fibrosis. I will
determine the association of fibrosis stages with hepatic ATRA and MerTK cleavage and determine whether
ATRA-induced MerTK cleavage is through activating P38 and the MerTK cleaving enzyme, ADAM17 in vivo.
This research will be accomplished in the setting of a comprehensive career development program designed to
provide me with the skills needed to achieve my career goal as an independent scientist in the field of liver
diseases. During the K99 phase, I will continue to gain expertise in molecular, cellular and biochemical
approaches to study NASH fibrosis at Columbia University. An advisory committee of established scient...

## Key facts

- **NIH application ID:** 10216245
- **Project number:** 5R00DK115778-04
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Bishuang Cai
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2020-07-16 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10216245

## Citation

> US National Institutes of Health, RePORTER application 10216245, MerTK in NASH-related liver fibrosis (5R00DK115778-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10216245. Licensed CC0.

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