SHP protein protecting the liver from inflammation.

Liver's Silent Guardian: How SHP Protein Can Prevent Hepatitis

Beau Callahan in Health & Wellness November 2025 • 4 min read.

"Unlocking the mysteries of SHP and its role in liver inflammation could transform hepatitis treatment."

Fulminant hepatitis (FH) is a severe form of liver failure with limited effective treatments. Small heterodimer partner (SHP, NR0B2), an atypical orphan nuclear receptor, regulates various biological processes. Recent studies have highlighted SHP's involvement in immune responses, particularly in the recruitment of neutrophils during liver inflammation. New insights into SHP's role in modulating liver inflammation could revolutionize therapeutic strategies.

Previous research indicates SHP's regulatory function in innate immunity, modulating pro-inflammatory cytokines through mediators like IRAK1, TRAF6, and NF-kB in macrophages. SHP deficiency exacerbates liver injury by affecting immune cells such as natural killer T cells and neutrophils, increasing susceptibility to conditions like binge drinking-induced liver damage. The link between SHP and neutrophil recruitment, driven by the chemokine CXCL2, is critical, setting the stage for targeted therapies.

This investigation aims to clarify the specific mechanisms of CXCL2 regulation by SHP in the liver and identify the types of cells involved in neutrophil recruitment during liver inflammation. By understanding SHP's role, new treatments for fulminant hepatitis can be developed.

SHP's Protective Role in Liver Inflammation

SHP protein protecting the liver from inflammation.

A new study used bone marrow (BM) chimeric mice to investigate the role of SHP. Shp knockout (KO) or wild-type (WT) bone marrow cells were transferred into sublethally-irradiated WT or Shp KO recipients, followed by intravenous injection of ConA (20-30 mg/kg). The KO recipient groups showed higher ConA-induced lethality than the WT recipient groups. Plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and inflammatory cytokine expressions were significantly higher in the KO recipients regardless of donor genotype.

Massively increased hepatocyte death in KO recipients, as determined by H&E and TUNEL staining, was observed after ConA challenge. Bone marrow chimera experiments and in vitro chemotaxis assay also showed that SHP-deficient hepatocytes have an enhanced ability to recruit neutrophils to the injured liver. In vitro promoter assays showed that SHP is a negative regulator of Cxcl2 transcription by interfering with c-Jun binding to the AP-1 site within the Cxcl2 promoter.

SHP Deficiency: Increases susceptibility to ConA-induced hepatitis.
Neutrophil Recruitment: Augmented in SHP-deficient liver parenchymal cells.
CXCL2 Regulation: SHP controls TNFa-induced CXCL2, but not CXCL1, expression in mouse hepatocytes.
Transcription Control: SHP regulates CXCL2 transcription through interaction with c-Jun.

Experiment results indicates that SHP deficiency in liver parenchymal cells significantly increases susceptibility to ConA-induced hepatitis. Bone marrow transplantation experiments showed that KO recipients experienced higher mortality rates and elevated liver enzyme levels (ALT and AST) after ConA injection. Histological analysis revealed increased hepatocyte death in SHP-deficient mice, highlighting SHP's protective role in liver inflammation.

The Future of Hepatitis Treatment

Modulating SHP activity might offer a novel approach for treating inflammatory liver diseases, including hepatitis. By understanding the intricate mechanisms of SHP's action, medical researchers can develop targeted therapies to harness its protective effects and improve patient outcomes.

About this Article -

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This article is based on research published under:

DOI-LINK: 10.1038/s41598-018-33660-z, Alternate LINK

Title: Small Heterodimer Partner Negatively Regulates C-X-C Motif Chemokine Ligand 2 In Hepatocytes During Liver Inflammation

Subject: Multidisciplinary

Journal: Scientific Reports

Publisher: Springer Science and Business Media LLC

Authors: Jung-Ran Noh, Yong-Hoon Kim, Don-Kyu Kim, Jung Hwan Hwang, Kyoung-Shim Kim, Dong-Hee Choi, Seon-Jin Lee, Hee Gu Lee, Tae Geol Lee, Hong-Lei Weng, Steven Dooley, Hueng-Sik Choi, Chul-Ho Lee

Published: 2018-10-15

Everything You Need To Know

What is the role of SHP in liver inflammation and immune response?

SHP, or small heterodimer partner, functions as a regulator in the body's immune response, particularly during liver inflammation. It influences innate immunity by modulating pro-inflammatory cytokines through mediators like IRAK1, TRAF6, and NF-kB in macrophages. When SHP is deficient, individuals become more susceptible to liver injury, affecting immune cells like natural killer T cells and neutrophils. This can increase vulnerability to conditions such as binge drinking-induced liver damage. The connection between SHP and neutrophil recruitment, driven by the chemokine CXCL2, is vital for potential targeted therapies.

What did the bone marrow chimera experiments reveal about the role of SHP in liver inflammation?

Experiments using bone marrow chimeric mice demonstrated that SHP-deficient recipients experienced higher mortality rates and elevated liver enzyme levels (ALT and AST) after ConA injection. Histological analysis further revealed increased hepatocyte death in these SHP-deficient mice. Specifically, SHP was found to negatively regulate Cxcl2 transcription by interfering with c-Jun binding to the AP-1 site within the Cxcl2 promoter, which suggests a critical role for SHP in controlling neutrophil recruitment to the liver.

How does SHP regulate CXCL2 expression in liver cells, and why is this significant?

SHP controls the expression of CXCL2, but not CXCL1, in mouse hepatocytes. This regulation is achieved through SHP's interaction with c-Jun, which affects CXCL2 transcription. Since CXCL2 is crucial for recruiting neutrophils to the liver during inflammation, SHP’s control over CXCL2 offers a potential target for therapies aimed at modulating liver inflammation. Therapeutics can be developed to enhance SHP's regulation of CXCL2, reducing excessive neutrophil recruitment and subsequent liver damage.

In what ways might modulating SHP activity lead to new hepatitis treatments?

Modulating the activity of SHP presents a potential avenue for the treatment of inflammatory liver diseases, including hepatitis. By understanding the detailed mechanisms through which SHP operates, medical researchers could devise targeted therapies to leverage its protective effects. One approach might involve developing drugs that enhance SHP's ability to regulate CXCL2, thereby reducing excessive neutrophil recruitment. Another strategy could focus on preventing or reversing SHP deficiency to restore its protective functions in the liver.

Why is understanding SHP important in the context of fulminant hepatitis and other liver diseases?

Fulminant hepatitis (FH) is a severe form of liver failure with limited effective treatments. SHP deficiency exacerbates liver injury by affecting immune cells such as natural killer T cells and neutrophils, increasing susceptibility to conditions like binge drinking-induced liver damage. Further research into the role of SHP could uncover additional mechanisms and therapeutic targets, offering new strategies to combat liver damage. Therapies could potentially include gene therapies to increase SHP expression or small molecule drugs to enhance its activity.