# The Role of HMGB1 in autophagy deficiency-induced liver pathology

> **NIH NIH R01** · TULANE UNIVERSITY OF LOUISIANA · 2020 · $407,228

## Abstract

Macroautophagy, hereafter referred to as autophagy, is an evolutionarily conserved intracellular
degradation mechanism involved in diverse biological activities and in the pathogenesis of many
diseases. The homeostatic importance of autophagy for the liver is indicated in the fact that
autophagy deficiency causes multiple liver pathologies, including hepatomegaly, injury, inflammation,
ductular reaction, fibrosis and tumorigenesis. What are being triggered by autophagy deficiency to
lead to these changes are largely unknown but understanding the involved mechanisms will provide
the insight not only on how autophagy maintains hepatic homeostasis, but also on how similar
processes occur in other chronic diseases, such as those caused by alcohol, hyper-nutrients, and
hepatic viruses.
 Toward that end, we have found that HMGB1 is actively released from autophagy-deficient
hepatocytes, which is different from the more commonly seen case of passive release from dead cells
during injury, but is similar to the active release by macrophages during inflammation. Regulatory
mechanisms including Nrf2 and Caspase1 affect HMGB1 release independently from liver injury.
HMGB1 acts in an extracellular mode and requires its receptor, RAGE, to regulate the ductular
reaction, i.e., the expansion of ductular cells (DRs), also known as hepatic progenitor cells (HPCs) or
oval cells, and to promote the development of hepatic tumors. These results indicate that hepatic
HMGB1 plays an important and unique role in the liver pathogenesis caused by autophagy deficiency.
 The proposal have three aims. In Aim 1 we will investigate the mechanism of HMGB1 release
from hepatocytes, addressing the hypothesis that inflammasomes are involved in the process. In Aim
2 we will examine the mechanism of ductular reaction promoted by HMGB1. In Aim 3 we will dissect
the mechanisms of HMGB1 in tumor progression by examining the hypothesis that HMGB1 may alter
the hepatic microenvironment. The successful completion of this work will reveal the novel roles of
hepatocyte-derived HMGB1 in hepatic homeostasis and the results may be generally applicable to
similar pathogenic processes in other types of chronic liver diseases, thus advancing the research in
this field.

## Key facts

- **NIH application ID:** 9928451
- **Project number:** 5R01DK116605-04
- **Recipient organization:** TULANE UNIVERSITY OF LOUISIANA
- **Principal Investigator:** XIAO-MING YIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $407,228
- **Award type:** 5
- **Project period:** 2018-07-26 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928451

## Citation

> US National Institutes of Health, RePORTER application 9928451, The Role of HMGB1 in autophagy deficiency-induced liver pathology (5R01DK116605-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928451. Licensed CC0.

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