# The role of hepatocyte necroptosis and inflammation in liver-brain crosstalk in aging

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2024 · $409,430

## Abstract

Project Summary
Chronic, low-grade inflammation (inflammaging) is a hallmark of aging and is one of the ‘seven pillars of aging’
associated with age-related diseases. Liver aging is characterized by an increase in chronic inflammation that is
associated with chronic liver diseases (CLD), a leading cause of liver transplantation and mortality in the elderly.
Liver inflammation and CLD are proposed to promote neuroinflammation and cognitive impairment in humans,
supporting a role of liver in cognitive dysfunction. Despite the link between the liver-brain inflammation axis,
pathway(s) promoting liver inflammation or how liver aging contributes to neuroinflammation or cognitive deficit
is not known. Necroptosis is a cell death pathway that releases damage associated molecular patterns (DAMPs
such as HMGB1) and promote inflammation through the activation innate immune cells. We found that
necroptosis increases with age in the liver of mice, and inhibiting necroptosis (using Ripk3-/- or Mlkl-/- mice or
pharmacological inhibitor) reduced HMGB1, proinflammatory M1 macrophages, proinflammatory cytokines, and
liver pathology (steatosis and fibrosis) in the liver of old mice. Necroptosis inhibition improved autophagy and
reduced cellular senescence, key pathways associated with inflammaging and liver pathology. Importantly,
activating necroptosis specifically in hepatocytes of adult mice (7-month-old) impaired autophagy and increased
cellular senescence, macrophage numbers, and proinflammatory cytokines in the liver. Together, these data
support the conclusion that necroptosis is a key factor in liver inflammation and pathology through activation of
macrophages and senescence in the liver. Our data show that hepatocyte-specific necroptosis increases
neuroinflammation (proinflammatory cytokines and glial cell activation) and levels of circulating HMGB1, a known
mediator of neuroinflammation. Neuroinflammation is a significant contributor to cognitive decline, and we found
that hepatocyte necroptosis reduced nest building capacity, an early indicator of behavioral deficits in mice.
Given that hepatocytes undergo age-related necroptosis and are the primary source to circulating HMGB1 in
liver diseases, the central hypothesis of the proposal is that necroptosis activation specifically in hepatocytes will
increase HMGB1 release from hepatocytes that will increase liver inflammation by activating macrophages, and
liver pathology by increasing cellular senescence. Circulating HMGB1, in turn, will promote neuroinflammation
and cognitive impairment through systemic effects. We will test this hypothesis using novel mouse models that
allow us to either inhibit or activate necroptosis specifically in hepatocytes. Aim 1. Determine the role of
hepatocyte specific necroptosis on macrophage activation and liver inflammation; Aim 2. Determine the role of
hepatocyte specific necroptosis on cellular senescence and liver pathology; Aim 3. Determine the effects of
hepatocyte sp...

## Key facts

- **NIH application ID:** 10980163
- **Project number:** 2R01AG059718-06A1
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** Deepa Sathyaseelan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $409,430
- **Award type:** 2
- **Project period:** 2019-05-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980163

## Citation

> US National Institutes of Health, RePORTER application 10980163, The role of hepatocyte necroptosis and inflammation in liver-brain crosstalk in aging (2R01AG059718-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10980163. Licensed CC0.

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