# Jagged-Notch signaling in NASH/fibrosis

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $559,719

## Abstract

Project Abstract
Obesity is the predominant risk factor for Non-Alcoholic Fatty Liver Disease (NAFLD), the leading cause for
chronic liver disease with prevalence approaching 30% in certain populations. NAFLD, however, may in fact be
considered a “pre-disease” state for Non-Alcoholic Steatohepatitis (NASH), which is defined by liver injury and
associated inflammation and fibrosis. NASH has no approved pharmacotherapy, and is thus the fastest-growing
reason for liver transplantation. As the prevalence of obesity-related NASH continues to rise, and available livers
for transplantation remain limiting, this unmet need grows more urgent.
In obese mice and patients undergoing liver biopsy for suspected NASH, we observed an unexpected and
aberrant activation of hepatocyte Notch, a morphogenic pathway critical for cell fate decision-making in normal
liver development. Validation studies revealed that Notch activity was positively associated with markers of
liver inflammation and fibrosis and tracked with disease severity in patients with pre- and post-intervention
biopsies in randomized clinical trials. Our mechanistic work in the first cycle of this grant showed that Notch is
causal to disease, as hepatocyte-specific Notch loss-of-function – by genetic or pharmacologic ablation of
either the Notch ligand Jagged1, or by blocking Notch transcriptional activity – protected mice from diet-
induced steatohepatitis and fibrosis, whereas forced Jagged1 or Notch activity exacerbated inflammation and
fibrosis phenotypes. To determine downstream factors responsible for Notch activity, we performed a series of
RNAseq and scRNAseq screens that revealed LTBP3 as a novel Notch target. In Aim 1, we study with novel
genetic and pharmacologic tools whether increased hepatocyte LTBP3 secretion mediates Notch-induced
hepatic inflammation and fibrosis, and potential mechanisms of these effects. Beyond endocrine
communication, hepatocytes can directly interact with non-parenchymal cells, including hepatic stellate cells
(HSC), to determine obesity-induced liver pathology. Intriguingly, we observed increased Notch activity in HSC
isolated from NASH diet-fed mice; other preliminary data suggest that the same proximal signal (Jagged1) may
mediate HSC activation and lead to liver fibrosis, which we test in Aim 2. Finally, we leverage a novel mouse
model of reversible hepatocyte Notch activity to discover potential fibrosis regression pathways in Aim 3.
Achieving the goals of this application will identify mechanistic determinants of Notch-induced liver pathology
and potentially lead to application of novel Jagged-Notch or LTBP3 inhibitors for NASH and fibrosis.

## Key facts

- **NIH application ID:** 10918305
- **Project number:** 5R01DK119767-06
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Utpal Pajvani
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $559,719
- **Award type:** 5
- **Project period:** 2019-02-15 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918305

## Citation

> US National Institutes of Health, RePORTER application 10918305, Jagged-Notch signaling in NASH/fibrosis (5R01DK119767-06). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10918305. Licensed CC0.

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