# Lipotoxicity and Liver Inflammation

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2022 · $357,750

## Abstract

PROJECT SUMMARY
Overall Objectives of this proposal are to define mechanisms linking hepatocyte injury during lipotoxicity with
hepatic inflammation in nonalcoholic steatohepatitis (NASH). NASH is the most common pediatric liver disease
characterized by abundant circulating saturated free fatty acids (SFAs), along with hepatocyte lipotoxicity and
monocyte-derived macrophage mediated liver inflammation. Hepatocyte lipotoxicity and liver injury are, in part,
induced by SFAs and their intracellular metabolite lysophosphatidyl choline (LPC). However, cellular and
molecular mechanisms linking hepatocyte lipotoxicity to liver inflammation are not completely understood.
Emerging data implicate extracellular vesicles (EVs) released during hepatocyte lipotoxic stress in liver
inflammation. In published and preliminary experiments, we have discovered that, lipotoxic hepatocytes
release a large number of proinflammatory EVs; these EVs are enriched with the adhesion molecule integrin
β1 (ITGβ1) and promote monocytes adhesion to liver sinusoidal endothelial cells (LSECs) in vitro. We also
demonstrated that the expression of ITGβ1 ligand, vascular cell adhesion molecule (VCAM) 1, on LSECs is
increased during lipotoxicity. Based on these novel observations, we have formulated the CENTRAL
HYPOTHESIS that lipotoxic hepatocytes release ITGβ1-enriched EVs that recruit and retain monocyte in the
liver promoting inflammation. We will employ current biochemical and cell biological approaches that include
microfluidic technology, Nanoscale flow cytometry, and 89Zirconium isotopically labelled EVs visualized with
positron emission tomography (PET) scan to test this hypothesis. Our independent SPECIFIC AIMS will test
three integrated hypotheses. First, we will demonstrate that hepatocyte lipotoxicity induces an active
conformation switch of ITGβ1, enhancing its endocytic trafficking and release into EVs. Second, we will define
the mechanism of increased VCAM1 expression during lipotoxicity. We will also directly test the hypothesis
that lipotoxic hepatocyte-derived EVs mediate monocytes adhesion to LSECs, through ITGβ1-VCAM1 binding
interaction, in vitro by using microfluidic technology. Third, using a mouse model of NASH, we will test the
hypothesis that pharmacological inhibition of integrin β1 or conditional deletion of endothelial VCAM1 is
protective against liver inflammation. We will also demonstrate that adoptively-transferred lipotoxic hepatocyte-
derived EVs home to the LSECs of recipient mice through their high affinity integrin β1cargo. We have
established the requisite cell and mouse models to study lipotoxicity, integrin signaling and EV biology. This
proposal is technically and conceptually innovative, as it seeks to integrate the molecular mechanisms
underlying hepatocyte injury, integrin activation and trafficking with liver inflammation, and links hepatic
pathophysiology with nanomedicine. This research has the potential to identify new therapeutic strat...

## Key facts

- **NIH application ID:** 10337075
- **Project number:** 5R01DK122948-03
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Samar Ibrahim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $357,750
- **Award type:** 5
- **Project period:** 2020-04-15 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10337075

## Citation

> US National Institutes of Health, RePORTER application 10337075, Lipotoxicity and Liver Inflammation (5R01DK122948-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10337075. Licensed CC0.

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