# Pathobiology of Liver Injury

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2022 · $418,693

## Abstract

PROJECT ABSTRACT. My long term career objective is to define the mechanisms of liver inflammation in
nonalcoholic steatohepatitis (NASH), the most-prevalent chronic liver disease in the United States of America.
NASH is characterized by endoplasmic reticulum (ER) stress, which results in release of proinflammatory
extracellular vesicles (EVs) from lipid overloaded (lipotoxic) hepatocytes. The contribution of recruited
monocyte-derived macrophages (MDMs) to the intrahepatic macrophage (IHM) pool increases in NASH and
the recruited MDMs play a pivotal role in inflammation. The current proposal examines the mechanistic link
between hepatocyte-derived EVs and specific MDM subsets. In preliminary studies we have identified that
activation of the lipotoxic ER stress activated endoribonuclease, inositol requiring enzyme 1 alpha (IRE1α) and
its target transcription factor X-box binding protein 1 (XBP1), upregulates the expression of S100A11. This
upregulation of S100A11 is associated with activating, histone 3 lysine 27, acetylation in the enhancer region
of S100A11. Lipotoxic hepatocytes release S100A11 containing EVs (S100A11-EVs). S100A11-EVs activate
macrophage receptor for advanced glycation endproducts (RAGE) signaling. Hepatocellular expression of
S100A11 and MDM expression of RAGE are upregulated in NASH. Silencing S100A11 decreases MDM-
associated hepatic inflammation in NASH. Based on these original preliminary data, we have formulated the
CENTRAL HYPOTHESIS that lipotoxic hepatocytes release S100A11-EVs which activate a subset of
proinflammatory RAGE expressing IHMs promoting NASH pathogenesis. Therefore, the goals of this
proposal are to understand: i) how S100A11-EVs are released by hepatocytes; ii) how RAGE is activated by
lipotoxic EVs in a subset of macrophages; and iii) can hepatic inflammation be attenuated by inhibiting
S100A11-EV-RAGE signaling? The proposed experiments will employ complementary in vitro and in vivo
models of lipotoxicity and NASH, and pharmacological, molecular and genetic approaches to address three
integrated hypotheses. First we will directly test the hypothesis that lipotoxic hepatocytes release S100A11-
EVs a) by XBP1 driven transcriptional upregulation of S100A11 by binding to and recruiting histone acetylating
factors to an enhancer region, and b) by selective cargo sorting of S100A11 into lipotoxic EVs. Second we will
directly test the hypothesis that RAGE is activated in a subset of macrophages by lipotoxic EVs a) by
generating multivalent signal competent RAGE oligomers, and b) leads to the accumulation of a subset of
proinflammatory RAGE expressing macrophages in the liver. Third we will directly test the hypothesis that
interrupting S100A11-EV induced RAGE activation attenuates murine NASH a) by reducing the release of
S100A11-EVs, and b) when macrophage RAGE is deleted. This R01 grant application will yield mechanistic
insights into hepatocyte-to-macrophage crosstalk in NASH, thus identifying potentially...

## Key facts

- **NIH application ID:** 10448449
- **Project number:** 5R01DK111378-07
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Harmeet Malhi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,693
- **Award type:** 5
- **Project period:** 2016-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10448449

## Citation

> US National Institutes of Health, RePORTER application 10448449, Pathobiology of Liver Injury (5R01DK111378-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10448449. Licensed CC0.

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