# Hepatic zinc deficiency dampens the acute phase response in patients with alcohol-associated hepatitis

## TL;DR

Low zinc levels in the liver of patients with alcohol-related hepatitis reduce the body's acute phase response, potentially worsening outcomes.

## Contribution

Identified a nine-gene zinc signature linked to reduced acute phase response in alcohol-associated hepatitis patients.

## Key findings

- Hepatic zinc deficiency is associated with down-regulation of acute phase response genes like SAA1 and CRP.
- Zinc depletion in macrophages and hepatocytes dampens the acute phase response to infection.
- Transcriptomic analysis confirmed a zinc signature in alcohol-associated liver disease datasets.

## Abstract

Zinc deficiency affects ~17% of the population globally, contributing to deficits in growth, metabolism and immunity. Serum zinc is greatly reduced in alcohol-associated hepatitis, driven by hepatic dysfunction and poor zinc retention. While zinc is an essential micronutrient with many beneficial anti-inflammatory and anti-oxidant properties, its role in the progression of alcohol-related liver disease (ALD) remains uncertain.

To identify broad transcriptomic responses to zinc, 11 publicly available datasets were examined to generate a transcriptomic zinc signature. Zinc signature genes were validated in vitro using primary immune cell and hepatocyte models supplemented with zinc or depleted of zinc using a S100A12 conjugated resin. The role of zinc deficiency in alcohol-associated hepatitis was examined bioinformatically, using large publicly available datasets, and confirmed in vitro.

A nine gene zinc signature consisting primarily of metallothonein genes identified hepatic zinc deficiency among ALD patients that was associated with a down-regulation of the acute phase response pathway (e.g., SAA1, CRP and C9 genes). In vitro studies using hepatocyte and immune cell cultures depleted of zinc demonstrated that macrophage induction of the acute phase response by LPS was dampened by zinc depletion.

Together, these data suggest that hepatic zinc stores among patients with alcohol-associated hepatitis are reduced, resulting in deficient acute-phase responses. Increasing hepatic zinc stores via supplementation and dietary modulation may improve acute responses to infection, and thus, long term outcomes in this patient group.

Flowchart illustrating a research process on zinc's role in gene stimulation and acute phase response. It begins with data mining to identify zinc-stimulated genes, followed by validation in vitro. Zinc's role is demonstrated in macrophages and hepatocytes during an infection, affecting cytokines IL-6 and IL-1β, and elements of acute phase response like SAA1 and CRP. The chart includes examining zinc signatures in alcohol-related liver disease datasets. Arrows guide the process flow.