Metabotropic Glutamate Receptor 3 Expression During Liver Disease Progression - Association with Inflammation and Cell Viability in Hepatocellular Carcinoma

Sep 22, 2026

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Hepatocellular carcinoma (HCC) is the most common liver cancer, typically developing on the background of cirrhosis and associated with high mortality, making early diagnosis essential. This study examined liver expression of metabotropic glutamate receptor 3 (mGluR3) during progression from fibrosis to cirrhosis and to HCC induced by diethylnitrosamine (DEN) in rats. mGluR3 (Grm3) mRNA increased in HCC, while protein rose significantly from cirrhosis onward and further in HCC, correlating with IL-6 and TGF-β transcripts and increasing serum and intrahepatic glutamate. Immunohistochemistry localized mGluR3 in hepatocytes and non-parenchymal cells. In HepG2 cells, glutamate and the group II agonist LY354740 inhibited forskolin-stimulated cAMP and increased viability without affecting dead cells, indicating mGluR3 involvement in inflammation-linked survival and potential biomarker and therapeutic targeting.

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Article Metabotropic Glutamate Receptor 3 Expression During Liver Disease Progression: Association with Inflammation and Cell Viability in Hepatocellular Carcinoma Ana Cristina García-Gaytán 1, Andy Hernández-Abrego 1, Dalia De Ita-Pérez 1, Ericka de los Ríos-Arellano 1, Emanuel Gámez 2, Mauricio Díaz-Muñoz 1 and Isabel Méndez 1, * Academic Editor: Paramjit S. Tappia Received: 19 March 2026 Revised: 23 April 2026 Accepted: 23 April 2026 Published: 27 April 2026 Copyright: © 2026 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. 1 Departamento de Neurobiología Celular y Molecular, Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Juriquilla 76230, Querétaro, Mexico; [andy.bha@comunidad.unam.mx](andy.bha@comunidad.unam.mx) (A.H.-A.); [daludek@hotmail.com](daludek@hotmail.com) (D.D.I.-P.); [erios.histologia.inb@gmail.com](erios.histologia.inb@gmail.com) (E.d.l.R.-A.); [mdiaz@comunidad.unam.mx](mdiaz@comunidad.unam.mx) (M.D.-M.) 2 Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara 44340, Jalisco, Mexico; [dremanuelgamez@hotmail.com](dremanuelgamez@hotmail.com) * Correspondence: [isabelcm@unam.mx](isabelcm@unam.mx); Tel.: +52-442-238-10-35 Abstract Hepatocellular carcinoma (HCC) is the most common type of liver cancer that is mostly preceded by cirrhosis, with a high mortality rate. Therefore, diagnosis is critical in the early stages. In this study, we explored the liver expression of metabotropic glutamate receptor 3 (mGluR3), a group II mGluR, during the progression from fibrosis to cirrhosis and, ultimately, to HCC induced by diethylnitrosamine (DEN) in rats. We found that mRNA expression of mGluR3 (Grm3) was upregulated in HCC, while the protein level was significantly increased from the cirrhosis stage, and even more in HCC. Grm3 correlated with interleukin-6 (Il6) and transforming growth factor-β (Tgfb) mRNA expression. Furthermore, serum and intrahepatic glutamate concentrations were augmented in HCC. Immunohistochemical analysis revealed that mGluR3 is expressed in hepatocytes and non-parenchymal cells (endothelial cells and macrophages), and we observed a positive signal in the cytoplasmic membrane, cytoplasm, and nuclei of tumor and non-tumor cells. We confirmed that normal hepatocytes (C9 cell line) express low levels of mGluR3 protein and HCC-derived cells (HepG2) express high levels of this receptor. Using HepG2 cells, we observed that mGluR3 activation by glutamate and the group II-selective agonist LY354740 treatments were functional, as both inhibited cAMP generation induced by forskolin and increased cellular viability with no effect on dead cells. These results showed that mGluR3 is differentially expressed throughout the progression of liver pathologies, is associated with the inflammatory environment, and plays a role in HCC cell survival, with potential utility as an early biomarker and therapeutic target. Keywords: glutamate; metabotropic glutamate receptor type 3; inflammation; fibrosis; cirrhosis; hepatocellular carcinoma 1. Introduction Glutamate is the major excitatory neurotransmitter in the brain and one of the most abundant amino acids in the blood. Its plasma concentrations are in the range of 50–100 mM [1] . This amino acid functions as both a biochemical intermediate and a messenger, since it mediates cellular responses through its binding to two classes of membrane receptors: ion channels, or ionotropic glutamate receptors (iGluRs), and G-protein-coupled receptors or metabotropic glutamate receptors (mGluRs) [2] . According to their pharmacology, amino acid sequence homology, and signal transduction pathways, mGluRs are classified into eight subtypes (mGluR1–8 and their genes GRM1–8) and divided into three groups: group I (mGluR1 and mGluR5), grou

FAQs

What was the study designed to investigate about mGluR3 in liver disease progression?

The study examined mGluR3 (Grm3) expression in the liver during progression from fibrosis to cirrhosis and ultimately to HCC in a rat model induced by diethylnitrosamine (DEN).

How did mGluR3 expression change from cirrhosis to hepatocellular carcinoma?

mRNA expression of Grm3 was upregulated in HCC, while protein levels increased significantly from the cirrhosis stage and were even higher in HCC.

What functional effects did mGluR3 activation have on hepatocellular carcinoma cells?

In HepG2 cells, glutamate and the group II-selective agonist LY354740 reduced forskolin-induced cAMP generation and increased cellular viability without affecting dead cells.

Sep 22, 2026

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